OA12597A - Processes and intermediates for preparing benzyl substituted epoxides. - Google Patents

Abstract

Disclosed are intermediates and processes for preparing epoxides of the formula (1): where R and PROT are defined herein. These epoxides are useful as intermediates in the production of biologically active compounds, i.e., in the production of pharmaceutical agents.

Description

012597

PROCESSES AND INTERMEDIATES FOR PREPARING BENZYL EPOXIDES

BACKGROUND OF THE INVENTION

This application daims priority from U.S. Provisional5 Application Serial No. 60/285,772, filed April 23, 2001. 1. Field of the Invention

The invention provides processes for preparing benzylsubstituted epoxides useful in the préparation of biologiçally 10 active compounds, as well as intermediates useful in thoseprocesses. 2. Description of the Related Art

International Publication W002/02512 discloses various15 hydroxyethylamines useful in treating Alzheimer's disease. Acommon intermediate in most of the products is an N-protectedepoxide. As a resuit, there exists a need for processes and intermediates that efficiently produce N-protected epoxides.

• Z -1- 012597

SUMMARY QF INVENTION

In a broad aspect, the invention provides cotnpounds of theformula II

where R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Ci-C6 alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, thio, -NRi0Rn where R10 andRu are independently hydrogen or Ci-C6 alkyl; cyano,trifluoromethyl, and Cx-C3 alkoxy, ~ (B) C2-C6 alkenyl or C2-C6 alkynyl, (C) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NRi2Ri3 where at each occurrence RX2 and R13 are the same or different and represent: (a) -H, (b) -Cx-C8 alkyl optionally substituted with one of : (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, - (Cx-C2 alkyl) - (C3-C8 cycloalkyl), - (Ci-C6 alkyl)-O-(Cx-C3 alkyl), -C2- C6 alkenyl, -C2-Ce alkynyl; and (E) C3-C7 cycloalkyl, -C(O) (Cx-C4 alkyl), -SO2NRx0Rn, -C(O)NRioRii, or -SO2(CX-C4 alkyl);

Ri is selected from: -2- 012597 (I) Ci-Ce alkyl optionally substituted with one halogen; (II) -CH2-CH=CH2; (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on the phenyl withnitro, halogen, or cyano; and R30 represents hydrogen or PROT, where PROT is a nitrogenprotecting group.

In another aspect, the invention provides amino alcoholsof the formula:

where R is as defined for Formula II above; andR2 is: chloro, bromo, or -Si(R2i)3 where each R2i is independently

Ci-C5 alkyl, -N(R23) (R24) where R23 and R24 are the same ordifferent and represent

Ci-C5 alkyl, or where NR23R24 represents piperidinyl,piperazinyl, or morpholinyl, phenyl optionally substituted with 1, 2, or 3 of Ci-C2 alkyl, with the proviso that at least one ofthe R2x groups is optionally substituted phenyl.

In another aspect the invention provides an unprotectedepoxide of formula V-unprotected -3- 012597 h2n

V-unprotected where R is as defined for Formula II.

The invention further provides a compound of formula XI

10 where Xi is chloro, bromo, or imidazolyl; and R and PROT are asdefined above for Formula II.

In another aspect, the invention provides a compound offormula XIV

where R, PROT and Ri are as defined above for Formula II. 15

In still another aspect, the mvcnu.for the préparation of an ester of formula II, where

PROT

20 the process comprises

(1) esterifying a protected amino acid of the formula I -4- 012597

PROT

where PROT and R are as defined above with an alkylating agentin the presence of a base.

In a related aspect, the invention provides anotherprocess for preparing esters of formula II:

PROT

10 where.Ri is an optionally substituted phenyl, the processcomprising: (a) forming a mixture of a protected amino acid of formulaI and an activating agent; (b) contacting the mixture .of (a) with a phénol optionally15 substituted on the phenyl ring with nitro, halogen, or cyano. 20

In another related aspect, the invention provides aprocess for the préparation of an ester of the formula II,which comprises treating a compound of formula XIV with “te hydrogen in the presence of a hydrogénation catalyst at apressure of from 1 atmosphère to about 100 psi, and preferablyin a suitable solvent.

The invention also provides a process for preparing a25 compound of formula III -5- 012597

where PROT, R, and R2 are as defined above for formula IV-unprotected, which comprises: (a) forming a mixture of an ester of formula II and adihalogenated methane, R2CH2X2, where R2 is as defined above andwhere X2 is -Br or -I; (b) adding a strong base having a pKb of greater thanabout 30 to the mixture from (a); (c) acidifying the mixture of (b).

In a related aspect, the invention provides another methodfor preparing a compound of formula III where PROT, R, and R2are as defined above. This method comprises: (a) forming a mixture of an acid R2-CH2-COOH and a base,preferably a strong base having a pKb of greater than about 30; (b) treating the mixture of (a) with an ester of formula11 ; and (c) acidifying the mixture from (b) .

In a still further related aspect, the invention providesa process for preparing ketones of formula III, wherein R2 isCl or Br, which comprises contacting a compound of formula XIwith LiCH2Cl or LiCH2Br.

In yet another aspect, the invention provides a processfor the préparation of a compound of formula XI. This processcomprises contacting a protected (S) amino acid of formula (I)with thionyl chloride, phosphorous trichloride, oxalylchloride, phosphorous tribromide, triphenylphosphorous -6- 012597 dibromide, oxalyl bromide, 1,2-phenylenetrichlorophosphate,2,4,6-trichloro-l,3,5-triazine or CDI.

In still yet another aspect, the invention provides a5 process for the préparation of a compound of formula (XX)

(XX) wherein RS7 is H, Ci-Cg alkyl, or benzyl;

Ri is - (CH2)i-2-S(O)0-2- (Ci-C6 alkyl), -CH2-CH2-S (O) 0_2-(Ci-Cg 10 alkyl) , or ___ Cj-Cg alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, -F, -Cl, -Br, -I, -OH, =O, -SH, -CsN, -CF3, -Ci-C3 alkoxy, amino,mono- or dialkylamino, -N(R)C(0)R'-, -OC(=O)-amino 15 and -OC(=0)-mono- or dialkylamino, or C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from halogen, -F, -Cl, -Br, -I, -OH, -SH, -CsN, -CF3, Ci-C3 alkoxy, amino, and mono- or 20 dialkylamino, or aryl, heteroaryl, heterocyclyl, -Ci-C6 alkyl-aryl, -Cx-Ce alkyl-heteroaryl, or -Cx-Cg alkyl-heterocyclyl, wherethe ring portions of each are optionally substitutedwith 1, 2, 3, or 4 groups independently selected from 25 halogen, -F, -Cl, -Br, -I, -OH, -SH, -CsN, -NR7R'7, -C(=0) - (C1-C4) alkyl, -S02-amino, -S02-mono ordialkylamino, -C(=0)-amino, -C(=0)-mono or -7- 012597 dialkylamino, -SO2-(Ci-C4) alkyl, -CO2R, -N(R)COR', or-N(R)SO2R'or -Ci-C6 alkoxy optionally substituted with 1, 2, or 3groups which are independently a selected fromhalogen, or C3-C7 cycloalkyl optionally substituted with 1, 2, or3 groups independently selected from halogen, -F, -Cl, -Br, -I, -OH, -SH, -CsN, -cf3, C1-C3 alkoxy, amino, Ci-Cs alkyl and mono- or dialkylamino, or Ci-Cio alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, -F,-Cl, -Br, -I, -OH, -SH, -CsN, -CF3, -C1-C3 alkoxy, amino, mono- or dialkylamino and -C1-C3alkyl, or C2-C6 alkenyl or C2-C6 alkynyl, each of which isoptionally substituted with 1, 2, or 3 groups independently selected from halogen, -F, -Cl, -Br, -I, -OH, -SH, -CsN, -CF3, C1-C3 alkoxy, amino, -Ci-C6 alkyl and mono- or dialkylamino;and the heterocyclyl group is optionally furthersubstituted with oxo; R7 and R-j' are independently H or -Ci-C6 alkyl; R2 and R3 are independently selected from the group consisting of H; Ci-C6 alkyl optionally substituted with one, two orthree substituents independently selected from the groupconsisting of C1-C3 alkyl, halogen, -OH, -SH, -CsN, -CF3,C1-C3 alkoxy, and -NR3oR31; - (CH2) 0-4-aryl ; - (CH2) 0-4-heteroaryl ; - (CH2)0-4-heterocycle; C2-C6 alkenyl optionallysubstituted with one, two or three substituentsindependently selected from the group consisting of -F,-Cl, -OH, -SH, -CsN, -CF3, C1.-C3 alkoxy, and -NR30R31; C2-C6alkynyl optionally substituted with one, two or three -8- 012597 substituents independently selected from the groupconsisting of -F, -Cl, -OH, -SH, -ON, -CF3, Cx-C3 alkoxy,and -NR3oR31; and -(CH2)o-«- C3-C7 cycloalkyl, wherein thecycloalkyl group is optionally substituted with one, twoor three substituents independently selected from thegroup consisting of -F, -Cl, -OH, -SH, -ON, -CF3, Ci-C3 . alkoxy, and -NR30R3i;or R2, R3 and the carbon to which they are attached form acarbocycle of three, four, five, six, or seven carbonatoms, wherein 1, 2, or 3 carbon atoms are optionally replaced by a heteroatom independently selected from thegroup consisting of -O-, -S-, -SO2-, and -NR22-; whereinR3o and R3i at each occurrence are independently H, or Ci-C6 alkyl; R22 is selected from the group consisting of -H, -Ci-C6alkyl, hydroxy Ci-C6 alkyl, amino Ci-C6 alkyl; haloCi-Ci alkyl; -C3-C7 cycloalkyl, - (Ci-C2 alkyl) - (C3-C7cycloalkyl), - (Cx-C6 alkyl)-O-(Ci-C3 alkyl), -C2-C6alkenyl, -C2-C6 alkynÿl, -Cx-C6 alkyl chain with onedouble bond and one triple bond, aryl, heteroaryl,and heterocycloalkyl;

Rc is selected from the group consisting of C1-C10 alkyloptionally substituted with 1, 2, or 3 groupsindependently selected from the group consisting of R205,~OC=O NR23SR240, "S (=0)o-2 Κ·235/ -NR23sC=O NR235R240, -C=ONR23sR240, and -S(=0)2 NR235R240; - (CH2) 0-3- (C3-C8) cycloalkylwherein the cycloalkyl is optionally substituted with 1, 2, or 3 groups independently selected from the groupconsisting of R205, -CO2H, and -CO2- (C1-C4 alkyl) ; - (CR24sR2so) 0-4-aryl ; - (CR245R2so) 0-4-heteroaryl, - (CR24SR25o) 0-4" heterocycloalkyl; - (CR245R250) 0-4-aryl-heteroaryl; - (CR24SR2so) 0-4-aryl-heterocycloalkyl; - (CR24sR2so) 0-4-aryl-aryl ; -9- 012597 - (CR245R250) o-4-heteroaryl-aryl ; - (CR245R250) 0-4-heteroaryl-heterocycloalkyl; - (CR245R2so) 0-4-heteroaryl-heteroaryl; -(CR245R250) ο-4-heterocycloalkyl-heteroaryl ; - (CR245R250) 0-4-heterocycloalkyl -heterocycloalkyl ; - (CR245R250) 0-4-heterocycloalkyl-aryl ; - (C (R255) (R260) ] 1-3-CO-N- (R2Ss) 2; -CH(aryl)2; -CH(heteroaryl)2; -CH (heterocycloalkyl)2; -CH(aryl) (heteroaryl) ; cyclopentyl, cyclohexyl,' orcycloheptyl ring fused to aryl, heteroaryl, orheterocycloalkyl wherein one carbon of the cyclopentyl,cyclohexyl, or cycloheptyl is optionally replaced with NH,NR215» O, or S (=0)0-2/ and wherein the cyclopentyl,cyclohexyl, or -cycloheptyl group can be optionallysubstituted with 1 or 2 groups that are independently R20sor =0; -CO-NR235R240? or -SO2- (C3.-C4 alkyl) ; C2-Cio alkenyloptionally substituted with 1, 2, or 3 R2os groups; C2-Ci0alkynyl optionally substituted with 1, 2, or 3 R2os groups;"- (CH2) 0-1-CH ( (CH2)o-6-OH) - (CH2) ο-l-aryl; - (CH2) 0-i-CHRC-6- (CH2) 0-x-heteroaryl; -CH(-aryl or -heteroaryl)-CO-O (Ci~C4 alkyl); -CH(-CH2-OH)-CH(OH)-phenyl-NO2, (Cx-C6 alkyl)-O-(Cx-Cgalkyl)-OH, -CH2-NH-CH2-CH (-O-CH2-CH3) 2. -H, and -(CH2)0-6-C (=NR235) (NR235R240) ; wherein each aryl is optionally substituted with 1, 2, or 3 R2Oo;each heteroaryl is optionally substituted with 1, 2, 3, or 4 R2oo ; each heterocycloalkyl is optionally substituted with 1, 2,3, or 4 R210; R2Oo at each occurrence is independently selected' from thegroup consisting of Cx-C6 alkyl optionallysubstituted with 1, 2, or 3 R205 groups; OH; -N02;halogen; -C02H; ChN; - (CH2) o-4-CO-NR220R225 ; - (CH2) 0-4-CO-(C1-C12 alkyl); - (CH2) 0-4-CO- (C2-C12 alkenyl); - (CH2) 0-4-CO-(C2-Cx2 alkynyl); - (CH2) 0.4-CO-(C3-C7 cycloalkyl); - (CH2) 0-4-CO-aryl ; - (CH2) 0-4-CO-heteroaryl ; - (CH2) 0-4-C0- -10- 012597 heterocycloalkyl ; - (CH2) o-4-CO-0-R2iS; - (CH2) 0-4-SO2-NR22oR225» ~ (CH2) 0-4-SO- (Ci~Ce alkyl); - (CH2) o-«-S02- (Cx-Ci2alkyl) ; - (CH2) 0-4-SO2- {C3-C7 cycloalkyl) ; - (CH2)0-4-N(Hor R215) -CO-O-R2i5; - (CH2) o-4“N (H OX R2is) -CO-N (R2is) 2; - (CH2)0-4-N-CS-N(R21s)2; - (CH2) 0-4-N{-H or R215)-CO-R220; - (CH2) o-4~NR22oR22s· - (CH2) 0-4-O-CO- (Ci-Ce alkyl) ; - (CH2) 0-4-O-P(O) - (OR240) 2; - (CH2)o-4-0-CO-N(R21s)2; - (ch2)0.4-o-cs-N(R2is)2; - (CH2) o-4-0- (R215) 2· ~ (CH2) o-4-0-(R2is) 2-COOH; - (CH2) 0-4-S-(R2is) 2; - (CH2) 0-4-0-(Ci-C6 alkyl optionallysubstituted with 1, 2, 3, or 5 -F); C3-C7 cycloalkyl;C2-C6 alkenyl optionally substituted with 1 or 2 R20sgroups; C2-Cç alkynyl optionally substituted with 1or 2 R2os groups; - <CH2)0-4~N(H or R2X5) -SO2-R220; and“(CH2)o-4- C3-C7 cycloalkyl; wherein each aryl group at each occurrence is optionally substituted with 1, 2, or 3 groupsthat are independently R20s, R210 or Ci-C6 alkylsubstituted with 1, 2, or 3 groups that areindependently R20s or R2io; wherein each heterocycloalkyl group at each occurrence is optionally substituted with 1, 2,or 3 groups that are independently R210; wherein each heteroaryl group at each occurrence isoptionally substituted with 1, 2, or 3 groupsthat are independently R2os» R210/ or Ci-C6 alkylsubstituted with 1, 2, or 3 groups that areindependently R205 or R2io; R2o5 at each occurrence is independently selected from thegroup consisting of Ci-C6 alkyl, halogen, -OH, -O-phenyl, -SH, -CsN, -CF3, Ci-C6 alkoxy, NH2, ΝΗ(0χ-06alkyl), and N-(Ci-C6 alkyl)(Cx-C6 alkyl); R210 at each occurrence is independently selected from thegroup consisting of Ci~C6 alkyl optionally -11- 012597 substituted with 1, 2, or 3 R2os groups; C2~C6 alkenyloptionally substituted with 1, 2, or 3 R2os groups;C2-C6 alkynyl optionally substituted with 1, 2, or 3R2o5 groups; halogen; Cx-C6 alkoxy; Ci-C6 haloalkoxy;-NR220R225; OH; CsN; C3-C7 cycloalkyl optionallysubstituted with 1, 2, or 3 R20s groups; -CO-(C1-C4alkyl) ; -S02.NR235R24o; -CO-NR23sR24o; -SO2- (C1-C4 alkyl) ;and =O; wherein R215 at each occurrence is independently selected frorathe group consisting of Ci-C6 alkyl, -(CH2)0-2~(aryl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C7cycloalkyl, and - (CH2) 0-2- (heteroaryl) , -(CH2)0-2-(heterocycloalkyl) ; wherein the aryl group ateach occurrence is optionally substituted with1, 2, or 3 groups that are independently R20s orR210; wherein the heterocycloalkyl group at eachoccurrence is optionally substituted with 1, 2,or 3 R210; wherein each heteroaryl group at eachoccurrence is optionally substituted with 1, 2,or 3 R2i0; R220 and R225 at each occurrence are independently selected from the group consisting of -H, -Ci-C6alkyl, hydroxy Ci-C6 alkyl, amino Ci-Cs alkyl;halo Cx-C6 alkyl; -C3-C7 cycloalkyl, -(Cx-C2alkyl)-(C3-C7 cycloalkyl), - (Ci-C6 alkyl)-O-(Ci-C3alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl, -Ci-C6alkyl chain with one double bond and one triplebond, -aryl, -heteroaryl, and -heterocycloalkyl;wherein the aryl group at each occurrence is optionally substituted with 1, 2, or 3groups that are independently R20s or R2io; -12- 012597 wherein the·heterocycloalkyl group at each occurrence is optionally substituted with1 » 2, or 3 R210 î wherein each heteroaryl group at each occurrenceis optionally substituted with 1, 2, or 3R210 ; R23S and R2«o at each occurrence are independently H, or Cx-C6 alkyl; R245 and R2so at each occurrence are independently selectedfrom the group consisting of H, C1-C4 alkyl, Cx-C4hydroxyalkyl, C1-C4 alkoxy, Cx-C4 haloalkoxy, »{CH2)o-4-C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, andphenyl; or R245 and R2bo are taken together with the carbon to which they are attached to form a carbocycle of 3, 4, 5, 6,or 7 carbon atoms, optionally where one carbon atomis replaced by a heteroatom selected from the groupconsisting of -O-, -S-, -S02-, and -NR220-; R255 and R26o at each occurrence are independently selectedfrom the group consisting of H; Cx-C6 alkyloptionally substituted with 1, 2, or 3 R20s groups;C2-C6 alkenyl optionally substituted with 1, 2, or 3R205 groups; C2-C6 alkynyl optionally substituted with1, 2, or 3 R20s groups; - (CH2) x.2-S (O) 0-2-(Cx-C6 alkyl); - (CH2) 0-4-C3-C7 cycloalkyl optionally substituted with1, 2, or 3 R205 groups; - (C1-C4 alkyl) -aryl; - (C1-C4alkyl)-heteroaryl; - (C1-C4 alkyl)-heterocycloalkyl;-aryl; -heteroaryl; -heterocycloalkyl; . (CH2) 1-4-R265-(CH2) 0-4-aryl ; - (CH2) 1-4-R26S-(CH2) 0_4-heteroaryl ; and; - (CH2) 1-4-R265- (CH2) 0-4-heterocycloalkyl ; wherein R2£s at each occurrence is independently -O-, -S- or-N(Cx-C6 alkyl)-; each aryl or phenyl is optionally substituted with 12, or 3 groups that are independently R20s, R210» -13- 012597 or Ci-C6 alkyl substituted with 1, 2, or 3groupe that are independently R205 or R2io; each heteroaryl is optionally substituted with 1, 2, 3, or 4 R200 · each heterocycloalkyl is optionally substituted with1, 2, 3, or 4 R2io; RK is -C (=0) - (CRR') 0-6^100/ R' 100, -SO2R'i00, - (CRR') i_6R'i00, -C(=O) - (CRR')-O-R'ioo, -C (=0) - (CRR')-S-R'100 or -C(=O)-(CRR* )-NRioo~R'100/ R1Oo and R'100 are independently aryl, heteroaryl, -aryl-W-aryl, -aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W-heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, -C (=0)-CH [ (CH2) 0- 2-O-R7] - (CH2) 0-2~aryl, -C(=O) -CH ( (CH2) 0-2-O-R7] - (CH2)0-2-heterocyclyl, or -C (=0)-CH [ (CH2) 0.2-O-R7] - (CH2) 0.2-'heteroaryl, where the ring portions of each are optionallysubstituted with 1, 2, or 3 groups independently selectedf rom -OR, -NO2, halogen, -CsN, -SR, -SO2Ri45, -C(=O)R, -OCF3, -CF3, -O-P(=0)(OR)(OR'), -N(R)(COR'), -N(R) (SOaRns) , - (CH2) o-4_CO-NRiosR' io5/ ~ (CH2) 0-4Ό- (CH2) 0-4-CONRR' , - (CH2) 0-4-CO- (Ci-Ci2 alkyl) , - (CH2) 0-4-CO- (C2-Ci2alkenyl) , - (CH2) 0.4-CO- (C2-C12 alkynyl) , - (CH2) 0.4-CO-(C3-C7 cycloalkyl) , - (CH2) 0-4-R110/ - (CH2) 0-4-R120/

- (CH2) 0-4"R130 / ~ (CH2) o-4-CO-Rho, - (CH2) 0-4-CO-R120Z - (CH2) 0-4-CO-R13o, - (CH2) o-4-CO-Ri4o, - (CH2) o-4“CO-0-Riso, - (CH2) 0-4-SO2-NRi05R' 105/ - (CH2) o-4"SO-(Ci~Cb alkyl), - (CH2)o-4-S02.(Ci-Ci2 alkyl), - (CH2) 0-4-SO2-(C3-C7cycloalkyl), - (CH2) 0.4-N (H or Ri50) -CO-O-Ri50, -(CH2)o-4-N(H or Riso)-CO-N (Riso) 2/ - <CH2) o-4-N (H or RiS0) -CS-N(RiS0)2, - (CH2) o-4"N (-H or Riso) "CO-R105/ -(CH2)o-4“NRiosR’ios/ ~ (CH2) o-4~Ri4o / ~ ( CH2) 0-4-O - CO - ( Ci - Ce alkyl), -14- 012597 - (CH2) 0-4-O-P (θ) “ (O-Rno) 21 ~ (CH2) 0-4“O-CO-N (R150) 2,-(CH2)0-4-0-CS-N(Riso)2, - (CH2)0-4-0-(R15o) , -(CH2)0-4-O-(Riss)-COOH, - (CH2) 0-4-S- (R150) , C3-C7 cycloalkyl, - (CH2)0-4-N(-H or Riso)-SO2-R7, or -(CH2)0-4- C3-C7cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or R100 is C1-C10 alkyl optionally substituted with 1, 2, or 3 Ru5groups, wherein

Rus at each occurrence is independently halogen, -OH, -CO2R, -Ci-C6 thioalkoxy, -CO2-phenyl, -NRiosR'7, -SO2-(Ci-Ce alkyl), -C(=0)Rieo, Rieo, -CONRiqsR' 105» -SO2NR105R'xosz -NH-CO-(Ci-C6 alkyl) , -NH-C(=0) -OH, -NH-C(=O) -OR, -NH-C(=O) -0-phenyl, -O-C(=O) - (Ci-C6 alkyl) ,-O-C(=0) -amino, -O-C(=0) -mono- or dialkylamino, -O-C(=O) -phenyl, -O-(Ci-C6 alkyl)-CO2H, -NH-SO2-(Ci-C6alkyl), Ci-Cfi alkoxy or Ci-Ce haloalkoxy; or R100 is - (Ci-C6 alkyl)-O-(Ci-C6 alkyl) or - (Ci-C6 alkyl)-S-(Ci-C6alkyl), each of which is optionally substituted with 1, 2,or 3 Rus groups, or R100 is - (C3-C8 cycloalkyl) optionally substituted with 1, 2, or3 Rus groups; R and R' independently are hydrogen; Ci-C6 alkyl optionally substituted with 1, 2, or 3 groups that are independentlyF, Cl, Br, or I; or - (Ci-C6) -Ruo; W is -(CH2)0-4-, -O-, -S (O) 0-2-, -N(R135)-, or -C(0)-; R7 and R7' are independently selected from the group consisting of H, Ci-C6 alkyl, C3-C7 cycloalkyl, C2-Ce alkenyl, C2-C6alkynyl, aryl, heteroaryl, and heterocyclyl,

Rios and R'ios are the same or different and represent -H, -Ruo,-R120, -C3-C7 cycloalkyl, -(Ci-C2 alkyl)- (C3-C7 cycloalkyl), - (Ci-C6 alkyl)-O-(Ci-C3 alkyl), -C2-C6 alkenyl, -C2-C6alkynyl, or -Ci-C6 alkyl Chain with one double bond andone triple bond, or -Ci-C6 alkyl optionally substituted with -OH or -NH2; or, -15- 012597 -Ci-C6 alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen;

Rias is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3.C7 cycloalkyl, - (CH2)0-2- (aryl) , - (CH2)0-2- (heteroaryl) , or- (CH2) 0-2- (heterocyclyl) , R140 is heterocyclyl optionally substituted with 1, 2, 3, or 4groups independently selected from Ci-C6 alkyl, Ci-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Ci-C6) alkylamino, di (Ci-C6) alkylamino, C2-C6 alkenyl, C2-C6alkynyl, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, amino (Ci-Ce) alkyl, mono (Ci-C6) alkylamino (Ci-C6) alkyl, di(Cx-C6) alkylamino (Ci-C6) alkyl, and =0;

Rus is Ci-Ce alkyl or CF3;

Riso is hydrogen, C3-C7 cycloalkyl, - (Ci-C2 alkyl) - (C3-C7 cycloalkyl), C2-Ce alkenyl, C2-C6 alkynyl, Ci-C6 alkyl withone double bond and one triple bond, -Ruo, -R120, or'Ci-Cg alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from -OH, -NH2, Cx-C3alkoxy, Ruo, and halogen; R1.55 is C3-C7 cycloalkyl, - (Cx-C2 alkyl) - (C3-C7 cycloalkyl), C2-C6alkenyl, C2-C6 alkynyl, Cx-C6 alkyl with one double bondand one triple bond, -Ruo, -RX2o, or

Cx-C6 alkyl optionally substituted with 1, 2, 3, or 4 groups independently selected from -OH, -NH2, Cx~C3alkoxy, and halogen;

Riso is selected from morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl, each of which isoptionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, hydroxy, cyano, C6) alkylamino, di (Cx-C6) alkylamino, C2-C6 alkenyl, C2-C6alkynyl, Cx-Ce haloalkyl, Cx-Ce haloalkoxy, amino (Cx-

Cx-C6 alkyl Cx-C6 alkoxy,nitro, amino, mono(Cx- -16- 012597 C6) alkyl, mono(Ci-C6)alkylamino(Ci-C6) alkyl, difCx-C6)alkylamino(Ci-C6) alkyl, and ®O;R110 is aryl optionallysubstituted with 1 or 2 R125 groupe, wherein, r125 at each occurrence is independently halogen, amino,mono- or dialkylamino, -OH, -ON, -SO2-NH2, -SO2-NH-Ci-C6 alkyl, -SOa-NCCx-Ce alkyl)2, -SO2- (Cx-C, alkyl), -CO-NH2, -CO-NH-Cx-Ce alkyl, or -CO-N(Cx-Ce alkyl)2; orCi-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with i, 2, or 3groups that are independently selected from Cx-C3 alkyl, halogen, -OH, -SH, -ON, -CF3, Cx-C3alkoxy, amino, and mono- and dialkylamino; or

Ci-C6 alkoxy optionally substituted with one, two orthree of halogen; R120 is heteroaryl, which is optionally substituted with 1— or 2 Ri25 groups; and R13o is heterocyclyl optionally substituted with 1 or 2 R125groups; comprising (a) reducing a ketone of formula III to generate analcohol of formula IV; and (b) treating the alcohol of formula IV with a base togenerate an epoxide.

In another aspect, the invention provides a process ofpreparing a compound of formula (XX), further comprisingcontacting the epoxide with an amine of formula RCNH(R57) toyield a protected amine of formula VII-l. further comprisingdeprotecting the protected amine of formula (VII-1.)

In another aspect, the invention provides a process ofpreparing a compound of formula (XX), further comprisingdeprotecting the protected amine of formula (VII-1) to generatea an amine or its acid addition sait of formula (VIII-l.) -17- 012597

In another aspect, the invention provides a process ofpreparing a compound of formula (XX), further comprising thedeprotected amine of formula VIII-l and forming an amide usingthe amine and a compound of the formula RNZ, wherein Z is CO2H, S COC1, -SO2Cl, a halogen, -O-mesylate, -O-tosylate, -O-nosylate,-O-brosylate, -O-trifluoromethanesulfonate, or CO-imidazolyl.In a more preferred embodiment, Z is CO2H. In an equallypreferred embodiment, Z is COCl. In yet another equallypreferred embodiment, Z is CO-imidazolyl. In yet another 10 equally preferred embodiment, Z is -SO2C1. In yet another equally preferred embodiment, Z is -O-mesylate, -O-tosylate,·-O-nosylate, -O-brosylate, or -O-trifluoromethanesulfonate. -18- 012597 10 15

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds of Formula II include those where R30is PROT and R is phenyl substituted with up to two groups Rpand Rq, where Rp and Rq independently represent (A) Cx-C6 alkyl optionally substituted with one, two orthree substituents independently selected from Cx-C3alkyl, halogen, hydroxy, -Ru where Rxo and Ru areindependently hydrogen or Cx-C6 alkyl,trifluoromethyl, and Cx-C3 alkoxy, (B) halogen, hydroxy, cyano, Cx-Ce alkoxy optionallysubstituted with 1, 2, or 3 fluoro, or (C) -NRX2RX3 where at each occurrence RX2 and RX3 are the same or different and represent hydrogen or alkyl.

More preferred compounds of Formula II are those ofFormula II-A

H PROT—

20 25 where PROT and Rx are defined as above.

Such compounds, i.e., compounds of Formula II-A, are preferredin the processes of the invention employing the esters.

Preferred Rx groups in II-A are Cx-Cs alkyl groupsoptionally substituted with one of bromo or chloro. Morepreferred are Cx-C4 groups optionally substituted with bromo orchloro, most preferably chloro.

Preferred compounds of Formula III include those ofFormula III-A -19- 012597 Ο PR0T-N\xX^z'R2

ΙΙΙ-Α where R, PROT and R2 are as defined above with respect toFormula II.

Such compounds, i.e., compounds of Formula III-A, are preferredin the processes of the invention employing compounds ofFormula III.

More preferred compounds of Formula III-A include thosewhere R is phenyl substituted with up to two groups Rp and Rq,where Rp and Rq independently represent (A) Ci-C6 alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, -NRi0Rn where Rlo and Ru areindependently hydrogen of’’ C!-C6 alkyl,trifluoromethyl, and Ci-C3 alkoxy, (B) halogen, hydroxy, cyano, Ci-Ce alkoxy optionallysubstituted with 1, 2, or 3 fluoro, or (C) -NR12R13 where at each occurrence R12 and R13 are the same or different and represent hydrogen or alkyl.

Particularly preferred compounds of Formula III-A arethose where Rp and Rq independently represent Ci-C2 alkyl,halogen, hydroxy, or Ci~C2 alkoxy. Still other particularlypreferred compounds of Formula III-A include those where Rp andRq independently represent halogen. A particularly preferredgroup of compounds represented by Formula III-A are those ofFormula III-B 20- 012597 PROT-N^Jl^Ra

III-B

Preferred PROT groups are t-butoxycarbonyl,benzyloxycarbonyl, * formyl, trityl, phthalimido,trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4- phenylbenzyloxycarbonyl,ethoxybenzyloxycarbonyl,chlorobenzyloxycarbonyl,chlorobenzyloxycarbonyl,bromobenzyloxycarbonyl,nitrobenzyloxycarbonyl, 2- methylbenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 3- chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 4- 4-2- 4- 4-2- (4- xenyl) isopropoxycarbonyl, 1,1-diphenyleth-l-yloxycarbonyl, 1,1-diphenylprop-l-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2- (p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1- methylcyclohexanyloxycabonyl, 2 -methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl) ethoxycarbonyl, 2- (methylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphino) ethoxycarbonyl, (trimethylsilylmethyl) prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4- acetoxybenzyloxycarbonyl, 2,2,2- trichloroethoxycarbonyl, 2 -ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4- (decyloxyl ) benzyloxycarbonyl, isobornyloxycarbonyl, 1 - piperidyloxycarbonyl, 9-fluoroenylmethyl carbonate, -CH-CH=CH2 and (-N=)CH-phenyl.

It is preferred that the nitrogen protecting group (PROT)be t-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ) , it ismore preferred that PROT be t-butoxycarbonyl. One skilled in -21- 012597 the art will understand the preferred methods of introducing at-butoxycarbonyl or benzyloxycarbonyl groupa and mayadditionally consult T. W. Green and P. G. M. Wuts in"Protective Groups in Organic Chemistry, 3rd édition" JohnWiley &amp; Sons, Inc. New York, N.Y., 1999 for guidance.

Preferred compounds of Formula IV-unprotected includethose of Formula IV-A-unprotected

OH

(IV-A-\inprotected) where R and R2 are defined as for Formula IV-unprotected.

Such compounds, i.e., compounds of Formula IV-A-unprotected,are preferred for use in the processes of the inventionemploying compounds of formula IV-unprotected.

Preferred compounds of Formula IV-A-unprotected includethose of Formula IV-B-unprotected

IV-B-unprotected where Rp and Rq independently represent (A) Ci-Ce alkyl optionally substituted with one, two or *, three substituents independently selected from Ci-C3alkyl, halogen, hydroxy, -NR10Rn where R10 and Ru areindependently hydrogen or Ci-C6 alkyl, trifluoromethyl, and Ci-C3 alkoxy, (B) halogen, hydroxy, cyano, Cx-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, or -22- 012597 (Cî -NR12Ri3 where at each occurrence Ri2 and RX3 are the same or different and represent hydrogen or alkyl.

Preferred Rp and Rq groupa in Formula IV-B-unprotected areindependently selected halogène. More preferably, Rp and Rqare fluorine atoms. Particularly preferred compounds of IV-B-unprotected are those where Rp and Rq are fluorine atoms in the 3- and 5-positions with respect to the point of attachment ofthe phenyl ring to the parent methylene.

Preferred compounds of Formula V-unprotected include thoseof Formula V-A-unprotected

R ' Formula V-A-unprotected where R is defined as above for Formula V-unprotected.

Such compounds, i.e., compounds of Formula V-A-unprotected, arepreferred in the processes of the invention employing compoundsof Formula V-unprotected.

Preferred compounds of Formula V-A-unprotected includethose where R is phenyl substituted with up to two groups Rpand Rq, where Rp and Rq independently represent (A) Ci-C6 alkyl optionally substituted with one, two orthree substituents independently selected from Cx-C3alkyl, halogen, hydroxy, -NR10Rxx where Rlo and Ru areindependently hydrogen or Cx-C6 alkyl,trifluoromethyl, and Ci-C3 alkoxy, (B) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, or (C) -NRi2Ri3 where at each occurrence R12 and Rn are the same of différent and represent hydrogen or alkyl. -23- 012597

Preferred Rp and Rg groupe in Formula V-A-unprotect'ed areindependently selected halogens. More preferably, Rp and Rgare fluorine atome. Particularly preferred compounde of V-A-unprotected are those where Rp and Rg are fluorine atoms in the3- and 5-poeitione with respect to the point of attachment ofthe phenyl ring to the parent methylene.

Preferred compounds of Formula XI include those of Formula

XI-A

O prot-n^AX| %

XI-A where R and Xx are as defined for Formula XI.

Such compounds, i.e., compounds of Formula XI-A, are preferredin the processes of the invention employing compounds ofFormula XI.

Preferred compounds of Formula XI-A include those where Ris phenyl substituted with up to two groups Rp and Rq, where Rpand Rg independently represent (A) Ci-C6 alkyl optionally substituted with one, two or three substituents independently selected from C3.-C3alkyl, halogen, hydroxy, -NRioRn where R10 and Rn areindependently hydrogen or Cx-C6 alkyl, trifluoromethyl, and C1-C3 alkoxy, (B) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, or (C) -NR12R13 where at each occurrence R12 and R13 are the same or different and represent hydrogen or alkyl. -24- 012597

Preferred Rp and Rq groupe in Formula XI-A areindependently selected halogens. More preferably, Rp and Rqare fluorine atoms, Particularly preferred compounds of XI-Aare those where Rp and Rq are fluorine atoms in the 3- and 5- 5 positions with respect to the point of attachment of the phenylring to the parent methylene.

Preferred compounds of Formula XIV include those where Ris phenyl substituted with up to two groups Rp and Rq, where Rp 10 and Rq independently represent (A) Ci-C6 alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, -NRi0Rn where Rio and Ru areindependently hydrogen or Ci-C6 alkyl, 15 trifluoromethyl, and Ci-C3 alkoxy, (B) halogen, hydroxy, cyano, Ci-Ce alkoxy optionallysubstituted with 1, 2, or 3 fluoro, or (C) -NRi2Ri3 where at each occurrence Ri2 and Rx3 are the same or different and represent hydrogen or alkyl. 20 Preferred Rp and Rq groups in Formula XIV are independently selected halogens. More preferably, Rp and Rqare fluorine atoms. Particularly preferred compounds of XIVare those where Rp and Rq are fluorine atoms in the 3- and 5-positions with respect to the point of attachment of the phenyl 25 ring to the parent methylene.

Other preferred compounds of Formula II are those ofFormula XV

O

-25- 012597

XV i.e., compounds of Formula II where R30 is hydrogen. Incotnpounds of Formula XV, Rx is as defined above with respect toFormula II.

Preferred alkylating agents for the estérification of I toII include (a) X4-Ci-C4 alkyl optionally substituted with one ofiodo, bromo, or chloro, preferably chloro; (a) dimethylsulfate; (b) X4-CH2-CH=CH2, (c) X4-CH2-phenyl where the phenyl ring is optionallysubstituted with nitro, halogen, cyano; and where X4 is iodo, bromo, chloro, -O-tosylate, -O-mesylateor -O-triflate.

Preferred compounds of Formula I are those having (S)stereochemistry and where R is phenyl substituted with twohalogen atoms, preferably fluorine atoms. Preferably the phenylis substituted in the 3- and 5- positions, more preferably withfluorine atoms in the 3- and 5-positions.

The following représentative compounds are listed to givethe reader an understanding of the compounds of formula X thatmay be prepared using the invention. Unless indicatedotherwise, ail names herein are generated using the AdvancedChemistry Development Inc. (ACD) nomenclature program, IUPACName Batch Version 4.5 or Version 5.09. N1-({IS, 2R)-l-benzyl-2-hydroxy-3-{[4-(trif luoromethyl) benzyl] aminojpropyl) -N3,N3-dipropylisophthalamide N1-{(IS,2R)-l-benzyl-3-[(2,3-dichlorobenzyl)arnino]-2-hydroxypropylJ -N3 ,N3-dipropylisophthalamide -26- 012597 N1- { (1S,2R) -l-benzyl-3- ί (3,5-dichlorobenzyl) amino] -2-hydroxypropyl} -N3, N3 - dipropylisophthalamide

Nx-{(1S,2R)-l-benzyl-3-[(3,5-difluorobenzyl)amino] -2-hydroxypropyl} -N3, N3-dipropylisophthalamide N1-( (1S,2R)-l-benzyl-2-hydroxy-3-{ [4-(trifluoromethoxy)benzyl] aminojpropyl) -N3,N3-dipropylisophthalamide N1-((1S,2R)-1- (3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino) -l-methyl-2-oxoethyl] amino}propyl) -N3,N3-dipropylisophthalamide N1- ( (1S,2R)-1- (3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino) -1-methyl-2-oxoethyl) aminojpropyl) -N3,N3-d ipropy1isophtha1ami de N3-((1S,2R)-1- (3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-2-(isobutylamino) -1-methyl-2-oxoethyl]aminojpropyl) -NS,N5-diprppyl-3,5-pyridinedicarboxamide N1- ( (1S.2R)-1-<3,5-difluorobenzyl)-2-hydroxy-3-{[2-(isobutylamino) -1, l-dimethyl-2-oxoethyl] aminojpropyl) -5-methylN3, N3 -dipropy 1 i sophthalamide N1- ( (1S, 2R) -1- (3,5-difluorotbenzyl) -2-hydroxy-3-{ [2-(isobutylamino) -2-oxoethyl] aminojpropyl) - 5-methyl-N3, N3-dipropylisophthalamide N1-t(1S,2R)-1- (3,5-difluorobenzyl)-2-hydroxy-3-({(1S)-1-[ (isobutylamino) carbonyl]propyl}amino)propyl] - 5-methyl-N3, N3 -dipropylisophthalamide N1- [ (1S,2R)-1- (3,5-difluorobenzyl)-2-hydroxy-3-({(IR)-1-[ {isobutylamino)carbonyl]propyl}amino)propyl]-5-methyl-N3, N3-dipropylisophthalamide N1- [ (1S,2R)-1-(3,5-difluorobenzyl)-3-(ethylamino)-2-hydroxypropyl ) - 5-methyl - N3, N3 - dipropylisophthalamide N1-[(1S, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-( i sobu t y 1 ami no ) propyl ] - 5 - methyl - N3, N3 - dipropy 1 i sopht ha 1 amide -27- 012597 N1-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{(3-(isobutylamino)-2-methyl-3-oxopropyl]amino}propyl)-5-methyl-N3, N3 -dipropylisophthalamide N1-((1S,2R)-1-{3,5-difluorobenzyl)-3-{[4-5 (dimethylamino)benzyl] amino} -2-hydroxypropyl) -5-methyl-N3,N3- dipropylisophthalamide N1-[(1S,2R)-3- { [ (1S)-l-benzyl-2-(isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl] -5-me t hy 1 - N3, N3 - d i pr opy 1 isophthalamide 10 N1-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(1S) -Ι- Ε (isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5-me t hyl - N3, N3 - dipropyl i soph t hal ami de N1-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2 -(dimethylamino) ethyl] amino} -2-hydroxypropyl) -5-methyl-N3,N3- 15 dipropylisophthalamide N1-{(1S,2R)-1- (3,5-difluorobenzyl)-2-hydroxy-3-[(3- pyridinylmethyl) amino] propyl} - 5-methyl-N3, N3-dipropylisophthalamide N1- [ (1S,2R)-3-{ [ (1S)-1- [ (benzyloxy)methyl]-2- 20 (isobutylamino)-2-oxoethyl]amino}-1-(3,5-difluorobenzyl) -2-hydr oxypropy 1 ] - 5 - methyl - N3, N3 - dipropyl i sopht ha 1 amide N1-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1-methyl1 -phenylethyl ) amino] propyl} -5 -methyl -N3, N3 -dipropylisophthalamide 25 N1-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({(IR)-1- [(isobutylamino)carbonyl]-2-methylpropyl}amino)propyl]-5-me t hy 1 - N3, N3 - dipropyl i sopht hal amide N1-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-(trifluoromethoxy) benzyl] amino}propyl) - 5-methyl-N3, N3 - 30 dipropylisophthalamide N1-!(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3- fluorobenzyl)amino]-2-hydroxypropyl}-5-methyl-N3, N3-dipropylisophthalamide -28- 012597 N1-{(1S, 2R)-1- (3,5-difluorobenzyl)-2-hydroxy-3-[(3- isopropoxybenzyl ) amino] propyl} - 5 -methyl -N3, N3 - dipropylisophthalamide

Schemes 1-7 general ly represent the processes of theinvention; while these schemes employ various preferredcompounds of the invention as intermediates and startingmaterials, it is to be understood that the processes are alsoapplicable to compounds not having the spécifie stereochemistryor substituent patterns depicted in the schemes. In summary: * Scheme 1 generally sets forth the process for thepréparation of the N-protected epoxide V from known amino acid(0). Epoxides of Formula V are useful as intermediates in theproduction of biologically active compounds, e.g.,pharmaceuticals for the treatment of Alzheimer’s Disease. _Scheme 2 discloses a process for the transformation of anepoxide V to the desired compounds of Formula X.

Scheme 3 discloses an alternative process for theconversion of the protected amino acid (I) to the correspondingketone (III) .

Scheme 4 discloses an alternative process to préparé theester (II).

Scheme 5 discloses a process to change the protectinggroup for the ester (II) .

Scheme 6 discloses a process to préparé the unprotectedalcohol (IV-unprotected) and the unprotected epoxide (V-unprotected).

Scheme 7 discloses a process for the transformation of anepoxide V-l to the desired compounds of Formula X-l.

Représentative examples of methods for preparing compoundsof the invention are set forth below. -29- 012597 SCHEME 1

estérification

alkylation PROT-N^Xj

OH epoxidation PROT-N^^x^Rz 1) réduction 2) separate diast.

(IV)

PROT-N^JÎ^Rj

asymmetric réduction epoxidation

OH PROT-N^A^Rs (IV-a)

SCHEME 2

-30- 012597 SCHEME 3 PROT' (I)

OH

SCHEME 4

CHO

(XU) (xm)

O (X3O)2-P\a°PROT-N ORi

O

PROT-N. A ORi

F (Π) -31- Q1259 7

BOC

F depro (Π-BOC) PROT-

OH -HN.À. R2

F (IV) SCHEME 5

SCHEME 6

OH

(IV-unprotected)

(V-unprotected) -32- 012597 SCHEME 7

5 The epoxides of formula V hâve two chiral centers; thus, compounds of Formula V can exist as any of four stereoisomers,i.e., two pairs of diastereomers. While biologically activeend products resuit from ail stereoisomers, the (S, S)configuration is particularly preferred. One of these chiral 10 centers in the epoxide (V) is derived from the starting aminoacid (0) . Therefore, it is preferred to start with the aminoacid (0) containing the desired enantiomeric center rather thanto start with a mixture and hâve to perform a resolution toobtain the desired (S)-enantiomer of the amino acid (0). 15 SCHEME 1 depicts the conversion of amino acid (O) to N-protected amino epoxide (V) . Protection of the free aminogroup of the preferably (S)-amino acid (0) with a nitrogenprotecting group (PROT) yields the protected amino acid (I) 20 having the same stereochemistry. Nitrogen protecting groupsare well known to those skilled in the art, see for example, -33- G12597 "Nitrogen Protecting Groups in Organic Synthesis", John Wileyand sons, New York, N.Y., 1981, Chapter 7; "Nitrogen ProtectingGroups in Organic Chemistry", Plénum Press, New York, N.Y.,1973, Chapter 2. See also, T. W. Green and P. G. M. Wuts in"Protective Groups in Organic Chemistry, 3rd édition" JohnWiley &amp; Sons, Inc. New York, N.Y., 1999. When the nitrogen protecting group is no longer needed, it may be removed.Suitable methods are known to those skilled in the art. Thereader's attention is again directed to the referencesmentioned above.

The protected amino acid (I) (preferably of (S)stereochemistry) is then converted to the correspondingprotected ester (II) (retaining the preferred (S)stereochemistry) . This conversion can be accomplished in avariety of ways.

When Ri is (a) Ci-C4 alkyl optionally substituted with one-Cl, "(b) -CH2-CH=CH2, or (c) phenyl optionally substituted withone nitro, halogen, or cyano conversion of I to II comprises: (1) esterifying a protected amino acid of the formula Iwith an alkylating agent in the presence of a base.

Suitable alkylating agents include (a) those represented by the formula X4-Ci~C4 alkyloptionally substituted with one -Cl where X4 is iodo,bromo, chloro, -O-tosylate, -O-mesylate or -O-triflate; (b) dimethylsulfate (c) X4-CH2-CH=CH2, where X4 is as defined above (d) a benzyl substituted on the methyl group with X4 where X4 is defined as above and where the phenyl ring isoptionally substituted with nitro, halogen, or cyano.

While a variety of bases are suitable for thisestérification, the base is preferably hydroxide, carbonate, -34- 012597 bicarbonate, LDA, n- (Ci-C8 alkyl)lithium, LiHMDS, NaHMDS orKHMDS. More preferably, the base is hydroxide, carbonate orbicarbonate. An even more preferred base is carbonate.

Preferred alkylating agents are dimethylsulfate, methyliodide, and methyl triflate. More preferably the alkylatingagent is dimethyl sulfate. When the base is LDA, n- (Ci-C8alkyl) lithium, LiHMDS, NaHMDS or KHMDS, a solution of the esteris preferably cooled to from about -78°C, and more preferablyabout -20’C, to about 25°C prior to the addition of the base.After addition of the alkylating agent, the mixture ispreferably heated to about 20°C to about 50°C. Heating isparticularly useful when the alkylating agent isdimethylsulfate.

Alternatively, when Rx is an optionally substituted benzylgroup, the estérification can be accomplished by (a) contacting a protected amino acid of formula (I)with an activating agent, i.e., activating the amino acid orforming an activated amino acid; and (b) adding to the mixture of (a) a phénol optionallysubstituted on the phenyl ring with nitro, halogen, or cyano.

The use of activating agents, such as for example, alkylchloroformâtes such as isobutyl chloroformate, CDI, and DCC, inestérification of acids with alcohols is well known to thoseskilled in the art. Preferred activating agents herein are CDIand DCC. Preferred esters in this process are those where Riis methyl or ethyl, more preferably methyl. A particularlypreferred ester is (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester. SCHEME 4 shows an alternate route to ester (II) . See alsoEXAMPLES 9 and 10. In the process of SCHEME 4, preferred 3,5-di fluorobenzaldéhyde (XII), which is commercially availablefrom, for example, Aldrich, Milwaukee, Wisconsin, USA, isreacted with the phosphorous compound (XIII), where X3 is a -35- 012597 suitable leaving group, to produce olefin (XIV). Suitableleaving groups are known to those skilled in the art. Aparticularly preferred olefin (XIV) is methyl (2Z)-2-[ [ (benzyloxy) carbonyl] -3- (3,5-difluorophenyl) -2-propenonate.

The phosphorous compounds (XIII) are known to thoseskilled in the art. X3 is preferably a Ci-C3 alkyl group, more,preferably methyl. The aldéhyde (XII) and the phosphorouscompound (XIII) are typically combined in a polar aproticorganic solvent, such as THF, MTBE, dioxane, ether or DME, andthe resulting mixture, preferably a solution, is then cooled toabout 0°. A base such as DBU or TMG is added and the contentsof the mixture warmed to about 20-25°C and stirred until thereaction is complété, i.e., preferably to greater than about90%, more preferably about 95%, and most preferably about 99%,conversion. Once the reaction is complété, the E- and Z-olefinisomers (XIV) are preferably separated since the Z isomer hasthe olefin stereochemistry preferred, and in some situationsnecessary, to yield the desired product. The séparation isaccomplished by methods known to those skilled in the art, suchas, for example, by silica gel chromatography.

Next the olefin (XIV) is hydrogenated with a suitablehydrogénation catalyst to obtain the desired ester (II) . Thereaction may be conducted at pressures of from about 1 to about100 psi. A variety of suitable catalysts will be recognized bythose having ordinary skill in the art. An example of a classof suitable catalysts is represented by the formula[Rh(diene) L]+X* where

Rh is rhodium; diene is cyelooctadiene and norbornadiene; L is a ligand selected from the group consisting ofDIPMAP, MeDuPhos, EtDuPhos, Binaphane, f-Binaphane,Me-KetalPhos, Me-f-KetalPhos, Et-f-KetalPhos, BINAP, -36- 012597 DIOP, BPPFA, BPPM, CHIRAPHOS, PROPHOS, NORPHOS,CYCLOPHOS, BDPP, DEGPHOS, PNNP and X' is C1O4', BF4', CF3-SO3·, Cl', Br', PF6' and SbF6*.

This class is preferred for use in this process aspect ofthe invention, particularly when L is DIPMAP or EtDuPhos.

Those skilled in the art will recognize suitable spécifieprocedures for this réduction, i.e., hydrogénation. Generally,olefin XIV is first dissolved in the solvent, either in thereaction vessel or the solution is later transferred to thevessel. Hydrogen and the desired catalyst are then introducedinto the vessel. The hydrogen is typically added underpressure, e.g., from about 25-75 psi of hydrogen. The catalystcan be added neat or as a solution of the catalyst in, forexample, methanol.

Some hydrogénation reactions will give racemic ester (II).Since the preferred stereochemistry of the ester (II) is (S)-,it is préférable to use the Z-olefin (XIV) with an appropriatehydrogénation catalyst. Suitable solvents for thehydrogénation include polar solvents such as THF and variousalcohols, preferably C1-C5 alcohols, and most preferablymethanol, éthanol, isopropanol. Another preferred solvent isTHF. The solvent is preferably degassed. Further, it ispréférable to purge the reaction vessel after dissolving theolefin (XIV) in the solvent and before introducing thecatalyst.

The hydrogénation is preferably a chiral hydrogénation andis performed in a température range of from about 0e to aboutreflux; it is preferred that the reaction be performed in thetempérature range from about 0° to about room température (20-25°) . The chiral hydrogénation is performed under a pressureof from about one atmosphère to about 100 psig. It ispreferred that the chiral hydrogénation be performed under apressure of from about 1 atmosphère to about 70 psig; it is -37- 012597 more preferred that the chiral hydrogénation be performed undera pressure of from about 10 psig to about 40 psig. The ester (II) is obtained in greater than 90% enantiomeric purity,preferably in greater than 95% enantiomeric purity.Hydrogénation can be performed in a variety of fashions, suchas, for example, in batch mode or in a continuous mode. SCHEME 5 and EXAMPLES 11 and 12 disclose another alternateprocess to préparé ester II. The process of SCHEME 5 permitsthe changing of one nitrogen protecting group for another andin addition provides the free amine XV. For example, if onehas a "BOC"-protected ester (II) and desires a "CBZ"-protectedester (II), the "BOC"-protected ester (II) is typically reactedwith an acid such as hydrochloric acid in a suitable solventsuch as methanol at températures of from about -20° to refluxto give the free amine (XV) . Preferably the amine XV is,methÿl (2S)-2-amino-3-(3,5-difluorophenyl)propionate. The freeamine (XV) is then protected with a different nitrogenprotecting group, such as "CBZ" to produce the correspondingand desired "CBZ"-protected ester (II).

The protected ester (II), preferably of (S) -stereochemisty, is then converted to the correspondingpreferably (S)-protected ketone (III) by any one of a number ofprocesses. R2 is preferably -Cl or -Br, more preferably R2 is -Cl.One of the processes for the transformation of the (S) -protected ester (II) to the corresponding (S)-protected ketone(III) is exemplified in EXAMPLE 16.

Generally, the protected ester (II) of preferably (S) -stereochemistry is combined with the dihalogenatedmethanereagent and to this mixture is then added a suitable base. Itis préférable to add the base to the mixture of ester anddihalogenatedmethane rather than the other way around. Next, -38- 012597 to the resuit ing base/ester/dihalogenatedmethane mixture isadded a second portion of base. It is preferred to add thesecond portion of base to the existing mixture. Finally, thebase/ester/dihalogenatedmethane is treated with acid. It ispreferred that X2 be -I. It is preferred that about 1 to about 1.5 équivalents of R2CH2X2 be used.

The strong base should hâve a pKb of greater than about 30. It is preferred that the strong base be selected from thegroup consisting of LD A, (Ci-Ce alkyl) lithium, LiHMDS, NaHMDSand KHMDS; it is more preferred that the strong base be LDA.It is preferred that strong base be présent in an amount offrom about 2 to about 2.5 équivalents.

Examples of the second base include compounds selectedfrom the group consisting of (C2-C4) alkyl lithium, phenyllithium, (Ci-C4) alkyl-Grignard and phenyl-Grignard. It ispreferred that the second base be selected from the groupconsisting of phenyl lithium, n-butyl lithium, methyl magnésiumbromide, methyl magnésium chloride, phenyl magnésium bromide orphenyl magnésium chloride; it is more preferred that the secondbase is n-butyl lithium. It is preferred that the second basebe présent in an amount of from about 1 to about 1.5équivalents.

Suitable acids are those, which hâve a pka of less thanabout 10. It is preferred the acid be selected from the groupconsisting of acetic, sulfuric, hydrochloric, citric,phosphoric, benzoic acids and mixtures thereof; it is morepreferred that the acid be hydrochloric or acetic acid. A variety of solvents are opérable for the process; thepreferred solvent for the process is THF. The reaction can beperformed in the température range from about -80° to about -50°; it is preferred to perform the reaction in the températurerange of from about -75° to about -65°. It is preferred that -39- 012597 the ketone (III) is tert-butyl (1S)-3-chloro-l-(3,5-dif luorobenzyl ) - 2 - oxopropy1 carbamate.

The process of transforming the (S)-protected ester (II)to the corresponding (S)-protected ketone (III) can also beperformed without the addition of a second base, see EXAMPLE 2.This process requires the presence of excess CH2(R2)X2 and threeor more équivalents of strong base, which has a pKb of greaterthan about 30 followed by adding acid.

In addition, the (S)-protected ester (II) and also betransformed to the corresponding ketone (III) in a processwhich comprises: (1) contacting R2-CH2-COOH with a strong base which has apKb of greater than about 30; (2) contacting the mixture of step (1) with an ester offormula (II); and (3) contacting the mixture of step (2) with an acid.

In this process it is preferred that the strong base isselected from the group consisting of LDA, (Ci-C8alkyl)lithium, LiHMDS, NaHMDS and KHMDS; it is more preferredthat the base is LDA. It is preferred that from about 2 toabout 2.5 équivalents of the strong base be used. The sameacids as discussed above are opérable here also, SCHEME 3 and EXAMPLE 15 sets forth an alternative way ofpreparing the ketone (III) from the amino acid (I) . Thisprocess first transforme the amino acid (I) to the intermediate(XI) and then transforme the intermediate (XI) to the desiredketone (III) . The transformation of the amino acid (I) to theintermediate (XI) comprises: (1) contacting a protected amino acid of formula (I) witha reagent selected from the group consisting of thionylchloride, SO2C12, phosphorous trichloride, oxalyl chloride,phosphorous tribromide, triphenylphosphorous dibromide, oxalylbromide, 1,2-phenylenetrichlorophosphate and 2,4,6-trichloro- -40- 012597 1,3,5-triazine. It is preferred that the reagent is thionylchloride or oxalyl chloride. The intermediate (XI) is notisolated. It is preferred that the intermediate (XI) is t-butyl- (IS) -2-chloro-l- [3,5-difluorobenzyl) -2-oxoethylcarbamate.Intermediate (IX) is then transformed to the desired ketone (III) in a process which comprises: (1) contacting a carbonyl compound of formula (XI) whereXi is -Cl, -Br and imidazolyl with LiCH2Cl or LiCH2Br. Thiscompound is then reacted with the anion derived from the CH2R2X2reagent. Various solvents are opérable as is known to thoseskilled in the art; the preferred solvent is THF. The reactionshould be performed in the cold, in a température range of fromabout -78° to about -50°.

The (S)-protected ketone (III) is then reduced to thecorresponding (S)-alcohol (IV) or (IV-a) by means known tothose skilled in the art for réduction of a ketone to thecorresponding secondary alcohol, see EXAMPLE 3. In addition,European Patent Application EP 0 963 972 A2 and InternationalPublication W002/02512 of PCT/US01/21012 disclose alternatereagents which are opérable and work well in the réduction.The réductions are carried out for a period of time betweenabout 1 hour and about 3 days at températures ranging fromabout -78° to elevated température up to the reflux point ofthe solvent employed. It is preferred to conduct the réductionbetween about -78° and about 0°. If borane is used, it may beemployed as a complex, for example, borane-methyl sulfidecomplex, borane-piperidine complex, or borane-tetrahydrofurancomplex. The preferred combination of reducing agents andreaction conditions needed are known to those skilled in theart, see for example, Larock, R.C. in Comprehensive OrganicTransformations, VCH Publishers, 1989.

The réduction of the (S)-protected compound (III) to thecorresponding alcohol (IV) produces a second chiral center and -41- 012597 produces a mixture of diastereomers at the second center, (s,R/S)-alcohol (IV). This diastereomeric mixture is thenseparated by means known to those skilled in the art such assélective low-température recrystallization or chromatographieséparation, most preferably by recrystallization, columnchromatrography or by employing commercially available chiralcolumns.

In another embodirnent, .e diastereomeric mixture producedby the non-selective réduction of the (S)-protected compound(III) is not separated but is directly converted into theepoxide. The epoxide diastereomers may then be separated intoby means well known in the art. Or, the epoxide diastereomersmay be reacted with the amine, RcNH(Rs7) to form compoundsanalogous to structure (VII-1, where Rc is 3-methoxybenzyl andR57 is H.) The diastereomers may be separated at this point,or further transformations may be carried out before thediastereomers are separated. For example, the séparation ofthe diastereomers can be carried out after deprotecting thealcohol (VII) to form the free amine (VIII) , or the séparationmay be carried out after the amine (VIII) is converted intostructure (X.)

Alternatively, the (S)-protected compound (III) may bereduced to selectively form the S or the R alcohol asillustrated in scheme I where the S alcohol is selectivelyformed. The sélective réduction will decrease the need for theséparation of the diastereomers as discussed above and willincrease the amount of the desired isomer that is formed.Idéally, a single diastereomer is formed during the réductionof the ketone to the alcohol and a séparation is not necessary.

The alcohol (IV) is transformed to the correspondingepoxide (V) by means known to those skilled in the art, seeScheme 6 (above) and EXAMPLE 4. The stereochemistry of the(S)-(IV) center is maintained in forming the epoxide (V). Apreferred means is by reaction with base, for example, but not -42- 012597 limited to, hydroxide ion generated from sodium hydroxide,potassium hydroxide, lithium hydroxide and the like. Reactionconditions include the use of Ci-Cg alcohol solvents; éthanolis preferred. Reactions are conducted at températures rangingfrom about -45° up to the reflux température of the alcoholemployed; preferred température ranges are between about -20°and about 40°.

The protected epoxides of amino acids (V) are known tothose skilled in the art as intermediates in the préparation ofpharmaceutical agents useful as renin and HIV inhibitors, seefor example US Patents 5,482,947, 5,508,294, 5,510,349,5,510,388, 5,521,219, 5,583,238, 5,610,190, 5,639,769,5,760,064 and 5,965,588. In addition, the protected epoxides (V) are intermediates useful in producing pharmaceuticalsagents to treat Alzheimer's disease. The epoxides (V) aretransformed to useful compounds by the procèss of SCHEMES 2 and3 and EXAMPLES 5 thru 8. The preferred compound is thecompound of EXAMPLE 8.

The unprotected epoxide (V-unprotected) is useful in thesame way. It can readily be protected to form the epoxide (V)or it can be reacted unprotected. In some instance the freeamino group may interfère in the subséquent reactions but inothers it will work quite well. In some instance it will bepossible to put the N-terminal end on first and then open theepoxide to produce the desired compounds (X).

The compounds (X) are amines and as such form salts whenreacted with acids. Pharmaceutically acceptable salts arepreferred over the corresponding compounds (X) since they oftenproduce compounds, which are more water soluble, stable and/ormore crystalline. Pharmaceutically acceptable salts are anysait which retains the activity of the parent compound and doesnot impart any deleterious or undesirable effect on the subjectto whom it is administered and in the context in which it is -43- 012597 administered. Pharmaceutically acceptable saits include saltsof both inorganic and organic acids. The preferred pharmaceuti-cally acceptable salts include salts of the following acidshydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,phosphoric, citric, methanesulfonic, CH3-(CH2)nl-C00H where nxis 0 thru 4, HOOC-(CH2) nx-COOH where nx is as defined above,HOOC-CH=CH-COOH, φ-COOH. For other acceptable salts, see Tnt.J. Pharm., 33, 201-217 (1986).

The compounds (X) and pharmaceutically acceptable saltsthereof are useful for treating humans who hâve Alzheimer'sdisease, for helping prevent or delay the onset of Alzheimer'sdisease, for treating patients with mild cognitive impairment(MCI) and prevent ing or delaying the onset of Alzheimer'sdisease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who hâveHereditary Cérébral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cérébral amyloid angiopathy and preventingits potential conséquences, i.e. single and récurrent lobarhemorrhages, for treating other dégénérâtive dementias,including dementias of mixed vascular and degenerative origin,dementia associated with Parkinson’s disease, dementiaassociated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration , diffuse Lewy bodytype of Alzheimer's disease. The compounds are preferably usedin the treatment, prévention and/or alleviation of Alzheimer'sdisease.

DEFINITIONS AND CONVENTIONS

The définitions and explanations below are for the terrasas used throughout this entire document including both thespécification and the daims. -44- Q12597

By "alkyl" and "Ci-C6 alkyl" in the présent invention ismeant straight or branched chain alkyl groupa having 1-6 carbonatoms, such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. It is understoodthat in cases where an alkyl chain of a substituent (e.g. of analkyl, alkoxy or alkenyl group) is shorter or longer than 6carbons, it will be so indicated in the second "C" as, forexample, *Ci-Cio’ indicates a maximum of 10 carbons.

By "alkoxy” and "Ci-C6 alkoxy" in the présent invention ismeant straight or.branched chain alkyl groups having 1-6 carbonatoms, attached through at least one divalent oxygen atom, suchas, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy,neopentoxy, hexoxy, and 3-methylpentoxy. JBy the term "halogen” in the présent invention is meantfluorine, bromine, chlorine, and iodine. "Alkenyl" and "C2-C6 alkenyl" means straight and branchedhydrocarbon radicale having from 2 to 6 carbon atoms and fromone to three double bonds and includes, for example, ethenyl,propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and thelike. "Alkynyl" and ”C2-C6 alkynyl" means straight and branchedhydrocarbon radicals having from 2 to 6 carbon atoms and one ortwo triple bonds and includes ethynyl, propynyl, butynyl,pentyn-2-yl and the like.

As used herein, the term "cycloalkyl" refers to saturatedcarbocyclic radicals having three to twelve carbon atoms. Thecycloalkyl can be monocyclic, or a polycyclic fused System.Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. Preferred cycloalkyl groups arecyclopentyl, cyclohexyl, and cycloheptyl. The cycloalkylgroups herein are unsubstituted or, as specified, substitutedin one or more substitutable positions with various groups. -45- Û12597

For example, such cycloalkyl groups may be optionallysubstituted with, for example, Ci-C6 alkyl, cx-C6 alkoxy,halogen, hydroxy, cyano, nitro, amino, mono (C!-C6) alkylamino,di (Ci-C6)alkylamino, C2-Cfialkenyl, C2-Cealkynyl, Ci-C6 haloalkyl,Ci-C6 haloalkoxy, amino (Ci-C6) alkyl, mono (Ci-C6) alkylamino (Ci-C6) alkyl or di (Ci-C6) alkylamino (Ci-C6) alkyl.

By "aryl" is meant an aromatic carbocyclic group having asingle ring (e.g., phenyl) , multiple rings (e.g., biphenyl), ormultiple condensed rings in which at least one is aromatic,(e.g.,· 1,2,3,4-tetrahydronaphthyl, naphthyl), which isoptionally mono-, di-, or trisubstituted. Preferred arylgroups of the présent invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl or6,7,8,9-tetrahydro-5H-benzoia]cycloheptenyl. The aryl groupsherein are unsubstituted or, as specified, substituted in oneor more substitutable positions with various groups. Forexample, such aryl groups may be optionally substituted with,for example, Ci-C6 alkyl, Ci-C6 alkoxy, halogen, hydroxy, cyano,nitro, amino, mono (Ci-C6) alkylamino, di (Ci-C6) alkylamino, C2-C6alkenyl, C2-C6alkynyl, Ci-C6 haloalkyl, Ci-C6 haloalkoxy,amino (Ci-Ce) alkyl, mono (Ci-C6) alkylamino (Ci-C6) alkyl or di (Ci-C6) alkylamino (Ci-C6) alkyl.

By "heteroaryl" is meant one or more aromatic ring Systemsof 5-, 6-, or 7-membered rings which includes fused ringSystems of 9-11 atoms containing at least one and up to fourheteroatoms selected from nitrogen, oxygen, or sulfur.Preferred heteroaryl groups of the présent invention includepyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl,indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, oxazolopyridinyl, imidazopyridinyl, -46- 0125 9 7 benzisoxazinyl,benzopyranyl, isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl, beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, 5 pyridopyridinyl, benzotetrahydrof uranyl, benzotetrahydrothienyl,purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl,imidazothiazolyl, dihydrobenzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, 10 benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroisoquinolinonÿl,dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl,benzodioxanyl, benzoxazolinonyl, pyrrolyl N-oxide, , pyrimidinyl15 N-oxide, pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxideL, indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-20 oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolylN-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolylN-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide,benzothiopyranyl S,S-dioxide. The heteroaryl groupa herein areunsubstituted or, as specified, substituted in one or more25 substitutable positions with various groups. For example, suchheteroaryl groups may be optionally substituted with, forexample, Cx-Ce alkyl, Cx-C6 alkoxy, halogen, hydroxy, cyano,nitro, amino, mono (Cx-C6) alkylamino, di (Cx-C6) alkylamino, C2-C6alkenyl, C2-C6alkynyl, Cx-C6 haloalkyl, Cx-C6 haloalkoxy,30 amino (Cx-Ce) alkyl, mono (Cx-C6) alkylamino (Cx~C6) alkyl or di(Cx-Ce) alkylamino (Cx-Ce) alkyl.

By "heterocycle", “heterocycloalkyl" or "heterocyclyl" ismeant one or more carbocyclic ring Systems of 4-, 5-, 6-, or 7-membered rings which includes fused ring Systems of 9-11 atoms -47- 012597 containing at least one and up to four heteroatoms selectedfrom nitrogen, oxygen, or sulfur. Preferred heterocycles ofthe présent invention include morpholinyl, thiomorpholinyl,thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide,piperazinyl, homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,tetrahydrothienyl,homothiomorpholinyl,oxazolidinonyl,dihydropyrazinyl, tetrahydrofuranyl,homomorpholinyl,S,S-dioxide,dihydropyrrolyl, piperidinyl,homopiperidinyl,homothiomorphol inyldihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide.The heterocycle groups herein are unsubstituted or, asspecified, substituted in one or more substitutable positionswith various groups. For example, such heterocycle groups maybe optionally substituted with, for example, Ci-C6 alkyl, Ci-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Ci-C6)alkylamino, di (Ci-C6) alkylamino, C2-C6alkenyl, C2-C6alkynyl,Ci-C6 haloalkyl, Ci-C6 haloalkoxy, amino (Ci-C6) alkyl, mono(Ci-C6) alkylamino (Ci-C6) alkyl, di (Cx-C6) alkylamino (Ci-C6) alkyl or=O.

Ail températures are in degrees Celsius. TLC refers to thin-layer chromatography. HPLC refers to high pressure liquid chromatography.THF refers to tetrahydrofuran. psig refers to pounds of pressure per square inch.CDI refers to 1,1'-carbonyldiimidazole. DCC refers to dicyclohexylcarbodiimide. TMG refers to 1,1,3,3-tetramethylquanidine. DMF refers to dimethylformamide. DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.DBN refers to 1,5-diazabicyclo[4.3.0]non-5-ene. LDA refers to lithium diisopropylamide. -48- 012597

LiHMDS, refers to lithium bis(trimethylsilyl)amide.

NaHMDS refers to sodium bis(trimethylsilyl)amide. KHMDS refers to potassium bis(trimethylsilyl)amide. BOC refers to t-butoxycarbonyl; 1,1-dimethylethoxy carbonyl ; (CH3) 3C-O-CO- .

Hunig's base refers to DIPEA, diisopropylethylamine, [ (ch3) 2ch] 2-n-ch2ch3 . DMAP refers to dimethylaminopyridine, (CH3) 2N-pyridin-l-yi.

Saline refers to an aqueous saturated sodium chloridesolution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support;eluent). Xt is understood that the appropriate fractions arepooled and concentrated to give the desired compound(s). CMR refers to C-13 magnetic résonance spectroscopy,Chemical shifts are reported in ppm (δ) downfield from TMS. NMR refers to nuclear (proton) magnetic résonancespectroscopy, Chemical shifts are reported in ppm (d) downfieldfrom TMS. TMS refers to trimethylsilyl. -φ refers to phenyl (C6H5) . MS refers to mass spectrometry expressed as m/e, m/z ormass/charge unit. (M + H] * refers to the positive ion of aparent plus a hydrogen atom. El refers to électron impact. CIrefers to Chemical ionization. FAB refers to fast atombombardment. ESMS refers to electrospray mass spectrometry. HRMS refers to high resolution mass spectrometry.

Pharmaceutically acceptable refers to those propertiesand/or substances which are acceptable to the patient from apharmacological/toxicological point of view and to themanufacturing pharmaceutical chëmist from a physical/chemical -49 012597 point of view regarding composition, formulation, stability,patient acceptance and bioavailability.

Pharmaceutically acceptable anion salts include salts ofthe following acids methanesulfonic, hydrochloric, hydrobromic,sulfurie, phosphoric, nitric, benzoic, citrie, tartaric,fumaric, maleic, CH3-(CH2în-COOH where n is 0 thru 4, HOOC-(CH2)n-COOH where n is as defined above. -O-mesylate refers to -O-methanesulfonic acid. -O-tosylate refers to -O-toluenesulfonic acid. -O-triflate refers to -O-trifluoroacetic acid.

When solvent pairs are used, the ratios of solvents usedare volume/volume (v/v).

When the solubility of a solid in a solvent is used theratio of the solid to the solvent is weight/volume (wt/v). DIPMAP refers tophenylphosphine]ethane.

MeDuPhos refers to dimethylphospholano)benzene. to (R, R)-1,2-bis[(o-methoxyphenyl)- ((2S, 5S) -2,5- 1,2-bis 1,2-bis

EtDuPhos refers dimethylphospholano)benzene.

Binaphane refers to (S,S)-1,2-Bis{S)-4,5-dihydro-3H-dinaphtho[2,l-c:l',2'-e]phosphepino}benzene. f-Binaphane refers to (R,R)-l,l'-Bis{R)-4,5-dihydro-3H-dinaphtho(2,l-c:l*,2’-e]phosphepino}ferrocene; "f" refers to ferrocenyl.

Me-KetalPhos refers to 1,2-Bis-[(2S,3S,4S,5S)-3,4-0-isopropylidene-3,4-dihydroxy-2,5-dimethyl]benzene.

Me-f-KetalPhos refers to 1,1'-Bis-[(2S,3S,4S,5S)-2,5-dimethyl-3,4-0-isopropylidene-3,4-dihydroxyphospholanyl]ferrocene.

Et-f-KetalPhos refers todiethyl-3,4-0-isopropylidene-3,4-dihydroxyphospholanyll ferrocene ((2S,5S)-2,5- 1,1'-Bis-[(2S,3S,4S,5S)-2,5- -50- G12597 BXNAP refers to fi-2,2' -bis(diphenylphosphino) - 1,1'binaphthyl. DIOP refers to (R,R) -2,3-0-isopropylidene-2,3-dihydroxy- 1,4-bis(diphenylphosphino)-butane. BPPPA refers to fi-i-[(S)-l'2- bisdiphenylphospino) f errocenyl] - ethyldimethylamine. BPPM refers to (2S,4S)-N-butoxycarbonyl-4- diphenylphosphino-2-diphenylphosphinomethylpyrrolidine.. CHIRAPHOS refers to (S, S)-2,3- bis(diphenylphosphino)butane. PROPHOS refers to (S) -1,2 -bis (diphenylphosphino) propane.NORPHOS refers to (R,fi)-5,6-bis(diphenylphosphino)-2- norbomene. CYCLOPHOS refers to fi-l-cyclohexyl-1,2- bis(diphenylphosphino)ethane. .BDPP refers to (2S,4S)-bis(diphenylphosphino)pentane.DEGPHOS refers to 1-substituted (S,S)-3,4-bis- (diphenylphosphino)- pyrrolidine. PNNP refers to N,N'-bis (diphenylphosphino) -N, N'-bis [ (fi) -1- phenyl1ethylenediamine.

Thionyl chloride refers to SOC12.

Phosphorous trichloride refers to PCI3.

Oxalyl chloride refers to (COC1)2.

Phosphorous tribromide refers to PBr3.

Triphenylphosphorous dibromide refers to <p3PBr2.

Oxalyl bromide refers to (COBr)2.

Ether refers to diethylether. 1,2-Phenylenetrichlorophosphate refers to

2,4,6-trichloro~l,3,5-triazine refers to -51- Q1259 7

Cl MTBE refers to methyl t-butyl ether. DME refers to dimethoxyethane.

The disclosures in this application of ail articles andreferences, including patents, are incorporated herein byreference.

The invention is illustrated further by the followingexamples, which are not to be construed as limiting theinvention in scope or spirit to the spécifie proceduresdescribed in them.

The starting materials and various intermediates may beobtained from commercial sources, prepared from commerciallyavailable organic compounds, or prepared using well-knownsynthetic methods.

EXAMPLES

The following detailed examples describe how to préparéthe various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative,and not limitations of the preceding disclosure. Those skilledin the art will recognize appropriate variations from theprocedures both as to reactants and as to reaction conditionsand techniques. EXAMPLE 1 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5- difluorophenyl)propanoic acid methyl ester (II) -52- { Q12597

Το a 1-L 3-neck round bottom flask equipped with amagnetic stirrer, nitrogen inlet and thermocouple is added 5 (2S)-2-I(tert-butoxycarbonyl)aminol-3-(3,5- difluorophenyDpropanoic acid (I, 40 g, 0.133 moles, 1équivalent) followed by THF (240 mL) . Lithium hydroxidemonohydrate (5.6 g, 0.133 moles, 1 équivalent) is added in asingle portion and is allowed to stir for 30 min at which time, 10 the contents are cooled to 0e. Once cooled, dimethyl sulfate(12.6 mL, 0.133 moles, 1 équivalent) is added dropwise viasyringe and then stirred for 30 min. The mixture is thenheated to about 50° and monitored (by HPLC) until 90%conversion had been achieved. At that time, the mixture is 15 cooled to below 20e (solids form) . The mixture is then pouredinto sodium bicarbonate (200 mL) , stirred for 15 min thenextracted with methyl t-butyl ether (200 mL) . The phases areseparated and the aqueous layer is extracted with methyl t-butyl ether (2 x 200 mL) . The combined organic phases are 20 washed with water (400 mL) dried over sodium sulfate, filteredand concentrated under reduced pressure to give a solid. Thismaterial is then recrystallized from hexanes to give the titlecompound, mp - 81°; NMR (DMSO-de) δ 7.51, 7.15-7.25, 4.43, 3.81, 3.00-3.26 and 1.49; CMR (DMSO-d6) Ô 172.43, 163.74, 25 161.20, 155.67, 142.58, 112.70, 120.23, 78.69, 54.71, 52.24, 39.25 and 28.37. -53- 012597 EXAMPLE 2 tert-butyl (IS)-3-chloro-l-(3,5-difluorobenzyl) -2-oxopropylcarbamate (III)

>

F

To a 1-L 3-neck round bottom flask equipped with amagnetic stirrer> nitrogen inlet, thermocouple and additionalfunnel is added (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester (II, EXAMPLE 1, 10.0g, 0.0317 moles, 1 équivalent) followed by THF (175 mL) thencooled to -78°. Once the mixture is cooled, iodochloromethane(9.25 mL, 0.127 moles, 4 équivalents) is added in one portionvia syringe. The addition funnel is charged with LDA (79 mL, 0.158 moles, 5 équivalents, 2.0 M in heptane/THF) and issubséquently added dropwise to the mixture keeping the internaitempérature below -70°. Once the addition is complété, thecontents are stirred for 15 min at which time acetic acid (47.2mL, 0.824 moles, 26 équivalents) is added dropwise via theaddition funnel keeping the internai température below -65°.Once this addition is complété, the mixture is stirred for 15min then warmed to 0° and poured into water (500 mL) , saline(500 mL) and methyl t-butyl ether (500 mL) then transferred toa separatory funnel. The phases are separated and t. a aqueousphase is extracted with methyl t-butyl ether (2 x 25C mL) . Thecombined organic phases are washed with saturated sodiumbicarbonate (500 mL) , sodium sulfite (500 mL) and water (500mL) . The organic phase is then dried over sodium sulfate,filtered and concentrated under reduced pressure to give a -54- 012597 solid. The solid is recrystallized from heptane/ï-propylalcohol (10/1)to give the title compound, mp « 139°; NMR (DMSO-.

d«) δ 7.47, 7.06-7.14, 4.78, 4.49, 3.20, 2.82 and 1.40,- CMR (DMSO-de) δ 200.87, 163.74, 161.20, 142.74, 112.80, 102.13, 79.04, 58.97, 47.72, 34.95 and 28.30. EXAMPLE 3 tert-butyl (IS, 2S)-3-chloro-l-(3,5- difluorobenzyl)-2-hydroxypropylcarbamate (IV)

_To a 250 mL 3-neck round bottom flask equipped withmagnetic stir bar, nitrogen inlet and thermocouple, is addedtert-butyl (IS)-3-chloro-l-(3,5-difluorobenzyl)-2- oxopropylcarbamate (III, EXAMPLE 2, 4.4 g, 0.0132 moles, 1équivalent) followed by THF (20 mL) and éthanol (30 mL) thencooled to -78°. Once the mixture is cooled, sodium borohydride(2.0 g, 0.0527 moles, 4 équivalents) is added as a solidportion wise over 30 min keeping the internai température below-70°. Once this addition is complété, the contents are stirredfor 2 hr at -78° then warmed to 0° and stirred an additional 1hr. The mixture is quenched by the addition of saturatedpotassium bisulfate (15 mL) and water (15 mL). This slurry isstirred for 30 min at 20-25° then concentrated under reducedpressure to half its volume. The mixture is then cooled to 0°and stirred for 30 min. After this time, the résultant solid#are collected by filtration and washed with water (2 x 50 mL)then dried under reduced pressure at 50° to give crude product.A syn/anti ratio of 4-9:1 has been observed. The desired -55- 0 T 25 9 7 product is recrystallized from hexanes/éthanol (25/1) to givethe title compound, mp = 149°; NMR (DMSO-d$) δ 6.89-7.16, 5.61,3.64-3.83, 3.19, 2.69 and 1.41; CMR (DMSO-dff) δ 163.67, 161.24,155.44, 112.70, 101.55, 78.04, 72.99, 54.29, 48.24, 35.97 and28.37. EXAMPLE 4 tert-Butyl (IS)-2-(3,5-difluorophenyl)-1-[(2S)- oxiranyl]ethylcarbamate (V)

To a 250 mL 3-neck round bottom flask equipped withmagnetic stir bar, nitrogen inlet and thermocouple, is addedtert-butyl (IS,2S)-3-chloro-l-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (IV, EXAMPLE 3, 3.5 g, 0.010 moles, 1équivalent) followed by absolute éthanol (60 mL) and cooled to0°. To this mixture is added potassium hydroxide (0.73 g, 0.013 moles, 1.25 équivalents) dissolved in absolute éthanol(10 mL) over 1 hr and the resulting suspension is warmed to 15-20° and stirred for 1 hr. At this time, water (100 mL) isadded and the reaction contents are cooled to -5° and stirredfor 30 min. The solids are collected by filtration and washedwith cold water (2 x 25 mL) then dried under reduced pressureat 45e to give the title compound, mp = 133°; NMR (DMSO-d6) δ7.03, 3.61, 2.68-2.98 and 1.33; CMR (DMSO-dJ δ 163.72, 161.29,155.55, 143.35, 112.65, 101.80, 78.17, 53.42, 52.71, 44.90,36.98 and 28.36.

The anti-diastereomer mp « 101°. -56- Q12597 EXAMPLE 5 tert-Butyl (1S, 2R)-1-(3,5-difluorobenzyl)-2- hydroxy-3- ( (3methoxybenzyl) amino]propylcarbamate(VII) tert-Butyl (1S)-2-(3,5-difluorophenyl)-1-((2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 4, 245 mg, 0.82 mmol) issuspended in isopropyl alcohol (6 mL) and 3-methoxybenzylamine(160 pL, 1.22 mmol) is added with stirring at 20-25°. Thismixture is heated to gentle reflux (bath temp 85°) undernitrogen for 2 hr, whereupon the resuiting mixture isconcentrated under reduced pressure to give the title compound.The title compound is purified by flash chromatography (2-5%methanol/methylene chloride; gradient élution) to give purifiedtitle compound. EXAMPLE 6 (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3- methoxybenzyl)amino)-2-butanol (VIII) tert-Butyl (IS, 2R)-l-(3,5-difluorobenzyl)-2-hydroxy-3- ((3-methoxybenzyl)aminojpropylcarbamate (VII, EXAMPLE 5, 258mg, 0.59 mmol) is dissolved in methylene chloride (1 mL) at 20-25°, and trifluoroacetic acid (1 mL) is added with stirringunder nitrogen. The mixture is stirred at 20-25° for"ï hr,whereupon the mixture is concentrated under reduced pressure togive the title compound. The title compound is used in thenext reaction without further purification. EXAMPLE 7 N1-{(IS,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- [(3-methoxybenzyl)amino]propyl}-5-methyl-N3, N3 -dipropylisophthalamide (X) (2R,3S)- 3-amino-4-(3,5-difluorophenyl)-1-((3-methoxybenzyl)amino)-2-butanol (VIII, EXAMPLE 6) is dissolved in anhydrous DMF (3 mL)and cooled to 0°. Triethylamine (500 pL, 3.6 mmol) and 5- -57 Q12597 methyl-W, W-dipropylisophthalamic acid (IX, 156 mg, 0.59 mmol)are added with stirring. The mixture is warmed to 20-25°briefly to allow for complété dissolution of the carboxylicacid, before recooling to 0°. 1-Hydroxybenzotriazole (157 mg, 1.2 mmol) is added with stirring, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (229 mg, 1.2 mmol) . The resuiting mixture is stirred at 0° for 5 min,then warmed to 20-25“ for 15 hr. The mixture is then quenched with aqueous citric acid (10%) , and the mixture extracted threetimes with ethyl acetate. The combined organic extracts arewashed with saturated sodium bicarbonate, saline, dried oversodium sulfate, filtered and concentrated under reducedpressure to give the title compound in crude form. Thismaterial is purified by flash chromatography (2-10%methanol/methylene chloride gradient elution) to give purifiedtitle compound, MS (ES) MH* = 582.3. EXAMPLE 8 N1-{ (IS,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3- [ (3-iodobenzyl) aminojpropyl} -5-methyl-N3, N3 -dipropylisophthalamide (X)

Following the general procedure of EXAMPLES 5, 6 and 7 andmaking non-critical variations but using 3-iodobenzylamine, thetitle compound is obtained. EXAMPLE 9 Methyl (2Z)-2-[((benzyloxy)carbonyl]-3-(3,5- difluorophenyl)-2-propenonate (XIV)

CHO NHCBz

-58- GÎ2597 3,5-Difluorobenzaldehyde (XII, 2.87 g, 0.02 moles, 1équivalent) and THF (100 mL) are mixed and cooled to about 0°.N- (Benzyloxycarbonyl)phosphonyl-glycinetrimethylester (XIII, 8.7 g, 0.026 moles, 1.3 équivalents) is added to the 3,5-difluorobenzaldéhyde (XII)/THF mixture. This is followed by 1,1,3,3-tetramethyl guanidine (4.0 mL, 0.032 moles, 1.56équivalents) added dropwise. The reaction is stirred for 5 minat 0° then allowed to warm to 20-25°. After 2 hr, the reactionis complété (by TLC analysis) at which time water (100 mL) andethyl acetate (100 mL) are added. The phases are separated andthe aqueous phase is extracted with ethyl acetate (100 mL) andthe combined organic phases are washed with saline (100 mL) ,dried over sodium sulfate, filtered and concentrated underreduced pressure to give a crude solid. The solid is purifiedby silica gel chromatography (ethyl acetate/hexanes; 15/85) togive-the title compound, mp « 112°; NMR (CDC13) δ 7.19, 7.06,6.86, 6.15, 6.43, 4.97 and 3.69; CMR (CDC13) Ô 165.56, 164.54,164.41, 162.07, 137.39, 136.02, 128.97, 128.80, 128.62, 128.57,128.47, 126.25, 112.57, 112.38, 105.22, 104.97, 104.72, 68.17and 53.33. Additional material ïs recovered that is a mixtureof E and Z olefins. EXAMPLE 10 methyl (2S)-2-{[ (benzyloxy) carbonyl] amino}-3-(3,5-difluorophenyl)propanoate (II)

Methyl (2Z)-2- [ ( (benzyloxy) carbonyl]-3-(3,5-difluorophenyl)-2-propenonate (XIV, XIV, EXAMPLE 9, 0.100 g,0.228 mmol) and degassed methanol (10 ml) are mixed in a 100 mLHastelloy bomb. The mixture is purged three times with hydrogen -59- 0.12597 (60 psig) and then stirred at 60 psig hydrogen for 60 min at20-25°. Then (R, R, ) -DIPAP)Rh (5.2 mg, 3 mole%) is dissolved inmethanol (1 mL, degassed) is added and the System purged withhydrogen (3 x 60 psig) . The contents are then stirred at 20 5 psig hydrogen at 25° overnight at which time the reaction iscomplété as determined by HPLC. The System is then purged andfiltered to remove the catalyst and the solvent is removedunder reduced pressure to give the title compound. 10 EXAMPLE 11 Methyl (2S)-2-amino-3-(3,5- difluorophenyl)propanoate (XV)

(2S) -2- [ ( tert-butoxycarbonyl)amino] -3- (3,5-difluorophenyl)propanoic acid methyl ester (II, EXAMPLE 1, 0.60 15 g (0.002 moles, 1 équivalent), methanol (20 mL) and hydrochloric acid (3N, 20 mL) are mixed. The mixture is thenheated to 50° and stirred until complété as measured by HPLC.When the reaction is complété, the contents are cooled to 20-25° and the pH of the mixture is adjusted to 8 with saturated 20 sodium bicarbonate and then concentrated under reduced pressure. This mixture is extracted with ethyl acetate (2 x 20mL) and the combined organic phases are dried over sodiumsulfate, filtered and concentrated, HPLC (Rétention time =2.89min; Zorbax RX-C8 acetonitrile/0.05M potassium dihydrogen 25 phosphate, 60/40; 1.0 mL/min, λ=210 nm.

This material is carried on without further purification into the next step. -60- 012597 EXAMPLE 12 Methyl (2S) -2- ( [ (benzyloxy) carbonyl] amino] -3 -(3,5-difluorophenyl)propanoate (II)

F F

Methyl ( 2S ) - 2 - amino- 3 - (3,5 -dif luorophenyl ) propanoate (XV,EXAMPLE 11, 0.300 g, 1.40 mmol, 1 équivalent) and water (10 mL)are mixed. Sodium carbonate (0.15 g, 1.40 mmol, 1 équivalent)of is added followed by benzylchloroformat'e (0.2 mL, 0.24 g, 10 1.4 mmol, 1 équivalent) and the mixture stirred at 20-25° until complété as measured by HPLC. Once the reaction is complété,ethyl acetate (20 mL) is added and the phases separated. Theaqueous phase is extracted with ethyl acetate (2 x 20 mL) , andthe combined organic phases are dried over sodium sulfate, 15 filtered, and concentrated. The concentrate is crystallizedfrom hexanes/ethyl acetate to give the title compound, mp -54°; NMR (DMSO-di) δ 7.84, 7.28, 7.06, 4.98, 4.35, 3.68, 3.12and 2.88. 20 EXAMPLE 13 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5- difluorophenyl)propanoic acid methyl ester (II) (2S)-2-I(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I, 5.0 g, 0.017 moles, 1.0 25 équivalent) and potassium carbonate (2.5 g, 0.018 moles, 1.1équivalent) are mixed in THF (100 mL) . To this heterogeneousmixture is then added dimethyl sulfate (1.6 mL, 2.1g, 0.017moles, 1.0 équivalent) and the contents were then stirred at20-25° overnight. Once the reaction is complété as measured by -61- 012597 HPLC, ammonium hydroxide (10%, 20 mL) is added and allowed tostir for 1 hr at which time the contents are extracted withethyl acetate (3 x 50 mL) . The combined organic phases arewashed with water (50 mL) and saline (50 mL) , dried over sodium 5 sulfate, filtered, and concentrated under reduced pressure togive the title compound. EXAMPLE 14 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5- difluorophenyl)propanoic acid methyl ester (II) 10 (2S) -2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (I, 5.0 g, 0.017 moles, 1.0équivalent) and potassium carbonate (2.5 g, 0.018 moles, 1.1équivalent) and DMF (100 mL) are mixed. To this heterogeneous 15 mixture is then added dimethyl sulfate (1.6 mL, 2.1 g, 0.017 moles, 1.0 équivalent) and the contents are then stirred at 20-25° overnight. Once the reaction is complété as measured byHPLC, ammonium hydroxide (10%, 20 mL) is added and allowed tostir for 1 hr. The contents are stirred for 30 min then cooled 2 0 to 0° and filtered. The solids are washed with cold water (20mL) and dried under reduced pressure to give the titlecompound. EXAMPLE 15 tert-butyl (IS)-3-chloro-l-(3,5-difluorobenzyl)- 25 2-oxopropylcarbamate (III) (2S) - 2- [(tert-butoxycarbonyl)amino] -3-(3,5-dif luorophenyl) propanoic acid (I) is dissolved in THF andstirred at 20-25°. Oxalyl chloride (1 équivalent) is added and 30 the mixture stirred for about 15 min to give t-butyl-(IS)-2-chloro-1- [3,5-dif luorobenzyl] -2-oxoethylcarbamate (XI). Themixture is cooled to <0° and LiCHICl (greater than 2équivalents) is added. The - mixture is stirred until the -62- 012597 reaction is complété. The reaction is quenched with water andthe product is extracted into ethyl acetate. The combinedorganic phases are washed with saline, dried over sodiumsulfate and concentrated under reduced pressure to give thetitle compound. EXAMPLE 16 tert-butyl (IS)-3-chloro-l-(3,5-difluorobenzyl)- 2-oxopropylcarbamate (III) ICH2CI (3.54 g, 1.46 mL, 19,.82 romol, 1.25 équivalent)and THF (5 mL) are added to (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acidmethyl ester (II, EXAMPLE 1, 5 g, 15.86 mmol, 1 équivalent).

The mixture is cooled to -78° and LDA (22.3 mL, 44.60 mmol, 2.25_equivalents, 2.0M) is added dropwise maintaining aninternai température below -60®. Once the addition iscomplété, the contents are stirred for 30 min at -78° at whichtime n-butyllithium (15.3 mL, 19.82 mmol, 1.25 équivalents; 1.3M in hexanes) is added dropwise maintaining an internaitempérature below about -60®. The reaction is stirred for 30miri then quenched into 0® hydrochloric acid (IN) . Ethylacetate is added and the phases are separated and the aqueousphase is extracted with ethyl acetate. The combined organicphases are washed with saturated sodium bicarbonate, dried oversodium sulfate, filtered and concentrated under reducedpressure to give the title compound, NMR (DMSO-dff) δ 7.47,7.06-7.14, 4.78, 4.49, 3.20, 2.82 and 1.40; CMR (DMSO-d6) 6200.87, 163.74, 161.20, 142.74, 112.80, 102.13, 79.04, 58.97,47.72, 34.95 and 28.30. EXAMPLE 17 . (2S,3S)-3-amino-l-chloro-4-(3,5- difluorophenyl)butan-2-ol -63- 012597 10 15 °Υ° ΟΗΗΝ. ^Cl

ΟΗ

tert-butyl (lS,2S)-3-chloro-1- (3,5-difluorobenzyl) -2-hydroxypropylcarbamate (IV,EXAMPLE 3, 1.0 gm, 2.98 mmol) and Dowex50WX2-400 resin (4.6 gm,23.8 mmol) and methanol (25 mL) are mixed. The mixture is thenplaced over a J-Kim shaker with heating at 50° for 2 hr. ESMSanalysis indicates no starting material left in the mixture.The reaction contents are filtered through a sintered funneland the resin washed with methanol (25 mL) andmethano1/methylene chloride (1/1, 25 mL) . The mixture is eluted with ammonia in methanol (2N, 2

The eluate is concentrated under reduced pressure to give thetitle compound, ESMS = 236.1. resultingx 25 mL) . EXAMPLE 18 (IS)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylamine

20 (IS, 2S) -3-chloro-l-(3,5-difluorobenzyl)-2-hydroxypropylamine (EXAMPLE 17, 3 3mg, 0.14 mmol) and absolute éthanol (1.5 mL) are mixed. Potassium hydroxide (9.8 mg, 0.175mmol) in absolute éthanol (0.5 mL) is added to this mixture andthe resulting mixture is stirred at 20-25 deg for 30 min. Atthis time ESMS indicates formation of the product (MH+ = -64- 012597 200.1). Water (2 mL) is added and mixture is concentratedunder reduced pressure to half the volume and then diluted withethyl acetate (15 mL) . The organic phase is separated and theaqueous phase is extracted with ethyl acetate (2 x 10 mL) . The 5 organic phases are combined, washed with saline and dried overanhydrous magnésium sulfate. The solvent is removed underreduced pressure to give the title compound, MH* = 200.1.

The invention and the manner and process of making andusing it, are now described in such full, clear, concise and 10 exact terms as to enable any person skilled in the art to whichit pertains, to make and use the same. It is to be understoodthat the foregoing describes preferred embodiments of theinvention and that modifications may be made therein withoutdeparting from the spirit or scope of the invention as set 15 forth in the daims. To particularly point out and distinctlyclaim the subject matter regarded as the invention, thefollowing daims conclude this spécification. -65-

Claims (117)

012597 What is claimed is:

1. A compound of the formula:

where R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Ci-C6 alkyl optionally substituted with one, two orthree substituents independently selected from C1-C3alkyl, halogen, hydroxy, thio, -NRi0Rn where Rio andRu are independently hydrogen or Ci-C6 alkyl, cyano,trifluoromethyl, and C1-C3 alkoxy, (B) C2-C6 alkenyl or C2-C6 alkynyl, - (C) halogen, hydroxy, cyano, Ci-Cs alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NRi2Ri3 where at each occurrence Ri2 and RX3 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of: (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-Ce alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, - (Ci-C2 alkyl) - (C3-Cecycloalkyl), -(Ci-C6 alkyl)-O-(Ci~C3 alkyl), -C2-Ce alkenyl, -C2-C6 alkynyl; and (E) C3-C7 cycloalkyl, -C(O)(Ci-C4 alkyl), -SO2NRi0Ru, -C (O) NRxoRix, or -SO2(Ci-C4 alkyl); Ri is selected from: (I) Ci-C6 alkyl optionally substituted with one halogen; (II) -CH2-CH=CH2; -66- 012597 (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on phenyl with nitro,halogen, or cyano; and R3o représente hydrogen or PROT, where PROT is a nitrogenprotecting group.

2. An ester of the formula (II) O PROT-N^U^R,

Ri isselected from: (I) Ci-C6 alkyl optionally substituted with one halogen; (II) —CH2-CH=CH2; (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on phenyl with nitro,halogen, or cyano; and PROT is a nitrogen protecting group.

3. An ester according to claim 1 where PROT is t-butoxycarbonyl.

4. An ester according to claim 1 where PROT isbenzyloxycarbonyl.

5. An ester according to claim 1 where Ri is Ci-C2 alkyl.

6. An ester according to claim 5 where Ri is Cx alkyl.' -67- 012597

7. An ester according to daim 1 which is selected fromthe group consisting of (2S) -2- [(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid methyl ester and methyl (2 S)-2- [ [ (benzyloxy)carbonyl]amino]-3-(3,5-di fluorophenyl)propanoate.

8. A compound of the formula OH where R2 is:chloro, bromo, or -Si(R2i)3 where each R2i is independently C1-C5 alkyl, -N(R23) (R24) where R23 and R24 are the same ordifferent and represent Ci-C5 alkyl, or where NR23R24 représente piperidinyl,piperazinyl, or morpholinyl, phenyl optionally substituted with 1, 2, or 3 of Cx-C2 alkyl, with the proviso that at least one ofthe R2x groups is optionally substituted phenyl.

9. A compound according to claim 8 where R2 is -Cl.

10 15 20 where PROT is as defined above, with an activating agent (2) contacting the mixture of (1) with a phenoxy compound of the formula (d) ΗΟ-φ where -<p is optionally substituted with one (A) -NO2, (B) -F, -Cl, -Br, -I, (C) -CsN.

10. A compound according to claim 8 where R2 is -Br.

11. A compound according to claim 8 which is (2S,3S)-3- amino-l-chloro-4-(3,5-difluorophenyl)butan-2-ol. -68- G12597

12. A compound of the formula:

13. A compound of the formula: O

where Xi is -Cl, -Br or imidazolyl; andPROT is a nitrogen protecting group. 10

14. A compound according to claim 13 where PROT is t- butoxycarbonyl or benzyloxycarbonyl.

15. A compound according to claim 13 where Χχ is -Cl. 15

16. A compound (XI) according to claim 13 where the compound is t-butyl-(lS)-2-chloro-l-[3,5-difluorobenzyl]-2-oxoethylcarbamate.

17. A compound of the formula:

18. A compound according to claim 17 where the PROT is tbutoxycarbonyl or benzyloxycarbonyl. 15

19. A compound according to claim 17 where Rx is Ci-C2 alkyl.

20. A compound according to claim 19 where Rx is Cxalkyl. 20

20 -69- 012597 10 where PROT is a nitrogen protecting group; and Ri is selected from: (I) Ci-C6 alkyl optionally substituted with one chloro; (II) -CH2-CH=CH2; (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on phenyl with nitro,halogen, or cyano.

21. A compound according to claim 17 which is methyl(2Z) -2- [ [ (benzyloxy) carbonyl) -3- (3,5-difluorophenyl) -2-propenonate. 25

22. A compound of the formula: O H2N^X0-R>

F where Ri is selected from: (I) Ci-C6 alkyl optionally substituted with one chloro; -70- 012597 (II) -CH2-CH=CH2; (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on phenyl with nitro,halogen, or cyano.

23. A compound according to claim 22 where Ri is Ci-C2alkyl.

24. A compound according to claim 23 where Ri is Cialkyl.

25 30 where Rx is an optionally substituted phenyl; R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Cx-C6 alkyl optionally substituted with one, two orthree substituents independently selected from Cx-C3alkyl, halogen, hydroxy, thio, -NRx0Rii where Rio and -102- 072597 Ru are independently hydrogen or Ci-C6 alkyl, cyano,trifluoromethyl, and C1-C3 alkoxy, (B) C2-C6 alkenyl or C2-C6 alkynyl, (C) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NR12R13 where at each occurrence Ri2 and Ri3 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of: (i> -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, __ (d) -C3-C8 cycloalkyl, - (Cx-C2 alkyl) - (C3-C8 cycloalkyl), - (Ci-C6 alkyl)-O-(C1-C3 alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl; and (E) C3-Ç7 cycloalkyl, -C(O) (C1-C4 alkyl), -SO2NRi0Rn,-C(O)NRioRn, or -SO2(CX-C« alkylF; and PROT is a nitrogen protecting group;the process comprising: (a) forming a mixture of an activating agent and aprotected amino acid of the formula PROT ΌΗ (b) contacting the mixture of (a) with a phénol optionallysubstituted on the phenyl ring with nitro, halogen, or cyano.

25. A compound according to claim. 22 which is methyl(2S) -2-amino-3- (3,5-difluorophenyl)propanoate.

26. A process for the préparation of an ester of theformula :

where Ri is selected from the group consisting of: (I) Ci-C4 alkyl optionally substituted with one -Cl; (II) -CH2-CH=CH2, and (III) benzyl optionally substituted on phenyl with nitro, halogen, or cyano; and PROT is a nitrogen protecting group, which process comprises: (a) contacting a protected amino acid of the formula (I) -71- 012597 ο PROT-Ν^Λθπ

where PROT is as defined above, with a base and (b) contacting the mixture of (a) with an alkylating agentof the formula (a) X4-C1-C4 alkyl optionally substituted with one ofiodo, bromo, or chloro; (a') dimethylsulfate; (b) X4-CH2-CH=CH2, (c) X4-benzyl where the phenyl ring is optionallysubstituted with nitro, halogen, cyano; and X4 is iodo, bromo, chloro, -O-tosylate, -O-mesylateor -O-triflate.

27. A process according to claim 26 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.

28. A process according to claim 26 where the base ishydroxide, carbonate, bicarbonate, LDA, n- (Ci-C8 alkyl)lithium,LiHMDS, NaHMDS or KHMDS.

29. A process according to claim 28 where the base ishydroxide, carbonate, or bicarbonate.

30. A process according to claim 29 where the base iscarbonate.

31. A process according to claim 26 where the alkylatingagent is dimethylsulfate, methyl iodide or methyl triflate. -72- 012597

32. A process according to claim 31 where the alkylatingagent is dimethylsulfate.

33. A process according to claim 26 where when the baseis LDA, n- (Cx-Ce alkyl) lithium, LiHMDS or KHDMS, and themixture of (a) is cooled to a range of from about -78° to about25e prior to the addition of the base.

34. A process according to claim 33 where the mixture of (a) is cooled to a range of from about -20° to about 25° priorto the addition of the base.

35. A process according to claim 26 where the mixture of (b) Ils heated from about 20e to about 50°.

36. A process according to claim 26where the ester (II) is (2S)-2-[(tert- butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acidmethyl ester.

37. A process for the préparation of an ester of theformula: O

where Ri is phenyl optionally substituted with one of nitro, halogen,or cyano; and — ... . PROT is a nitrogen protecting group, which process comprises: -73- 012597 (1) contacting a protected amino acid of the formula (I)O ΡΚΟΤ-Ν^ΛθΗ

38. A process according to claim 37 where PROT is t-butoxycarbonyl and benzyloxycarbonyl.

39. A process according to claim 37 where the activatingagent is CDI.

40. A process according to claim 37 where the activatingagent is DCC.

41. A process for the préparation of a ketone of formula III : O PROT-NXJ<^R2

42. A process according to claim 41 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.

43. A process according to claim 41 where Rx is Ci-C2alkyl.

44. A process according to claim 43 where Rx is Ci alkyl.

45. A process according to claim 41 wheré R2 is chloro orbromo.

-46. A process according to claim 45 where R2 is chloro.

47. A process according to claim 41 where CH2R2X2 isprésent in an amount of from about 1 to about 1.5 équivalentsbased on the amount of ester II.

48. A process according to claim 41 where X2 is iodo.

49. A process according to claim 41 where the strong baseis LDA, (Ci-Ce alkyl)lithium, LiHMDS, NaHMDS or KHMDS.

50. A process according to claim· 49 where the strong baseis LDA.

51. A process according to claim 41 where the strong baseis présent in an amount of from about 2 to about 2.5équivalents based on the amount of ester II. -76- 012597

52. A process according to claim 41 where a secondportion of base is added, where the second portion of base is{C1-C4) alkyl lithium, phenyl lithium, ( Ci-C4) alkyl-Grignard orphenyl-Grignard. 5

53. A process according to claim 52 where the second baseis phenyl lithium, n-butyl lithium, sec-butyllithium, tert-butyllithium, methyllithium, methyl magnésium bromidé, methylmagnésium chloride, phenyl magnésium bromide or phenyl 10 magnésium chloride.

54. A process according to claim 53 where the second baseis π-butyl lithium.

55. A process according to claim 41 where amount of thesecond is from about 1 to about 1.5 équivalents based on theamount of the ester II.

56. A process according to claim 41 where the acidifyingis carried out using an acid having a pKa of less than about10.

57. A process according to claim 56 where the acid isselected from the group consisting of acetic, sulfuric, 25 hydrochloric, citric, phosphoric, nitric, paratoluenesulfonic,and benzoic acids and mixtures thereof.

58. A process according to claim 57 where the acid ishydrochloric acid or acetic acid.

59. A process for according to claim 41 where the ketone(III) is tert-butyl (IS)-3-chloro-l-(3,5-difluorobenzyl)-2-oxopropylcarbamate. -77- 012597

60. A process for the préparation of a ketone of formula (III) O PROT-N^^il^Ra

where PROT is a nitrogen protecting group, andwhere R2 is -Cl or -Br, which process comprises: (a) contacting an acid R2-CH2-COOH, where R2 is as defined10 above, with a base; „ (b) contacting the mixture of (a) with an ester of formula (II) O PROT-N. JL V^ORi F F (II) 15 where Rx is selected from the group consisting of : (I) Ci-Ci alkyl optionally substituted with one -Cl; (II) -CH2-CH=CH2, (III) phenyl optionally substituted with one: (A) -NO2, 20 (B) -F, -Cl, -Br, -I, (C) -CsN, and (IV) -CH2-<p where the -φ ring is optionallysubstituted with (A) -N02, -78- 012597 (B) -F, -Cl, -Br, -I, (C) -ON and where PROT is as defined above; and (c) acidifying the mixture of (b) .

61. A process according to claim 60 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.

62. alkyl. A process according to claim 60 where Ri is Ci-C2

63. A process according to claim 62 where Ri is Ci alkyl. 15 64. bromo.

A process according to claim 60 where r2 is chloro or

65. A process according to claim 64 where r2 is chloro.

66. A process according to claim 60 where the base is a 20 strong base and is LD A, (Ci-CB alkyl)lithium, LiHMDS, NaHMDS or KHMDS.

67. A process according to claim 66 where the strong baseis LDA. 25

68. A process according to claim 60 where the strong baseis présent in an amount of from about 3 to about 3.5équivalents based on the amount of ester II. 30

69. A process according to claim 60 where the acidifying is carried out using an acid having a pKa of less than about10. -79- 012597

70. A process according to claim 69 where the acid isselected from the group consisting of acetic, sulfuric,hydrochloric, citrie, phosphoric and benzoic acids and mixturesthereof.

71. A process according to claim 70 where the acid ishydrochloric or acetic acid.

72. A process for the préparation of a compound of10 formula (XI) O prot-n^JL· i X1

where Xj is where Xx is -Cl, -Br or imidazolyl;where PROT is a nitrogen protecting group, 15 which process comprises (1) contacting a protected amino acid of formula (I) O PROT-hL JL

where PROT is as defined above, 20 with thionyl chloride, SO2C12, phosphorous trichloride, oxalylchloride, phosphorous tribromide, triphenylphosphorousdibromide, oxalyl bromide, 1,2-phenylenetrichlorophosphate,2,4,6-trichloro-l,3,5-triazine or CDI. -80- 012597

73. A process according to claim 72 where PROT is t-butoxycarbonyl or benzyloxycarbonyl.

74. A process according to claim 72 where Χχ is chloro.

-74- 012597 where PROT is a nitrogen protecting group, and R2 is: chloro, bromo, or -Si (Rai) 3 where each R2i is independentlyC1-C5 alkyl, -N(R23) (R24) where R23 and R24 are the same ordifferent and representCx-C5 alkyl, or where NR23R24 représente piperidinyl,piperazinyl, or morpholinyl, phenyl optionally substituted with 1, 2, or 3 of Cx-C2 alkyl, with the proviso that at least one ofthe R2i groups is optionally substituted phenyl, which process comprises: (a) forming a mixture of an ester of formula II and adihalogenated methane, R2CH2X2, where R2 is as defined above andwhere X2 is -Br or -I; O

where Ri is selected from the group consisting of: (I) C1-C4 alkyl optionally substituted with one -Cl; (II) -CH2-CH=CH2, (III) phenyl optionally substituted with onenitro, halogen, or cyano; and (IV) benzyl optionally substituted on phenylwith nitro, halogen, or cyano; and -75- 012597 PROT is as defined above, (b) adding a base to the mixture from (a) ; (c) acidifying the mixture of (b) .

75. A process according to claim 72 where the compound offormula XI is contacted with thionyl chloride or oxalylchloride.

76. A process according to claim 72 where the processproduces t-butyl- (IS) -2-chloro-l- [3,5-difluorobenzyl] -2-oxoethylcarbamate.

77. A process for the préparation of ketone of formula (III) PROT-N^X^R2 (III) where R2 is -Cl or -Br; and PROT is a nitrogen protecting group, which process comprises: (1) contacting a compound of formula (XI) PROT-NV:ZXXi (XI) -81- Û12597 where Xi is -Cl, -Br and imidazolyl; and PROT is as defined above,with LiCH2Cl or LiCH2Br.

78. A process according to claim 77 where PROT is t-butoxycarbonÿl or benzyloxycarbonyl.

79. A process according to claim 77 where Xx is chloro.

80. A process according to claim 77 where R2 is chloro.

81. A process according to claim 77 where the process produces tert-butyl (IS)-3-chloro-l-(3,5-difluorobenzyl) -2-oxopropylcarbamate.

82 . A process for the préparation of an ester of theformula (II) O prot-ν^Λο^ V' F (II) where Ri is selected from the group consisting of: (I) Ci-C4 alkyl optionally substituted with one -Cl; (II) -CH2-CH=CH2, (IIÎ) phenyl optionally substituted with one: (A) -NO2, (B) -F, -Cl, -Br, -I, (C) -C=N, -82- 012597 (IV) -CH2-<p where the -φ ring is optionally substituted with (A) -NO2, (B) -F, -Cl, -Br, -I, (C) -C=N; and PROT is a nitrogen protecting group, which process comprises: (b) treating a compound of formula XIV

where Ri and PROT are as defined above; and in a solvent with hydrogen in the presence of a hydrogénationcatalyst at a pressure of from 1 atmosphère to about 100 psi.

83. A process according to claim 82 where the PROT is t-butoxycarbonyl or benzyloxycarbonyl.

84. A process according to claim 82 where Ri is Ci-C2alkyl.

85. A process according to claim 84 where Ri is Ci alkyl.

86. A process according to claim 82 where the solvent ofstep (a) is degassed.

87. A process according to claim 82 where the reactionvessel is purged of oxygen after step (1) and before step (2). -83- 012597

88. A process according to claim 69 where thehydrogénation catalyst is a compound of the formula[Rh (diene) L]*X" where Rh is rhodium; where diene is cyclootediene and nonbornadiene; where L is DIPMAP, MeDuPhos, EtDuPhos, Binaphane, f- Binaphane, Me-KetalPhos, Me-f-KetalPhos, Et-f-KetalPhos, BINAP,DIOP, BPPFA, BPPM, CHIRAPHOS, PROPHOS, NORPHOS, CYCLOPHOS,BDPP, DEGPHOS, PNNP and where X' is C1O4', BF4', CF3-SO3', Cl', Br', pf6' and SbF6'.

89. A process according to claim 88 where the hydrogenat ion catalyst is DIPMAP.

90. A process according to claim 88 where the hydrogénation catalyst is EtDuPhos.

91. A process according to claim 82 where the reaction température is from about 0° to about reflux

92. A process according to claim 91 where the reaction température is from about 0° to about 25°.

93. A process according to claim 82 where the reaction pressure is from about 1 atmosphère to about 70 psig.

94 . A process according to claim 93 where the reaction pressure is from about 10 psig to about 40 psig.

95. A process according to claim 82 where the ester (II) is obtained in greater than 90% enantiomeric purity.

96. A process according to claim 95 where the -84- 012597 ester (II) is obtained in greater than 95% enantiomericpurity.

-97- 0.1259 7 where R is phenyl optionally substituted with 1, 2, 3, or 4 groupeindependently selected from: (A) Ci-Ce alkyl optionally substituted with one, two orthree substituents independently selected from Cx-C3alkyl, halogen, hydroxy, thio, -NR10Rxx where Rlo andRu-are independently hydrogen or Ci-C6 alkyl, cyano,trifluoromethyl, and Cx-C3 alkoxy, (B) C2-C6 alkenyl or C2-C6 alkynyl, (C) halogen, hydroxy, cyano, Cx-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) —NR12R33 where at each occurrence R12 and R13 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of: (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-Ce alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, - (Ci-C2 alkyl)- (C3-C8cycloalkyl) , - (Cx-C6 alkyl)-O-(Cx-C3 alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl; and (E) C3-C7 cycloalkyl, -Ç(O) (Cx-C4 alkyl), -SO2NR10Rn, -C (O)NRioRn, or -SO2(Ci-C4 alkyl).

97. A process according to daim 82 where theester (II) is methyl (2S)-2-{((benzyloxy)carbonyllamino}-3-(3,5-di fluorophenyl)propanoate.

98. A process for preparing an epoxide of formula V-R

cotnprising (a) converting an ester of Formula II into a ketone offormula III; (b) reducing the ketone to the corresponding alcohol offormula IV; and (c) treating the alcohol with a base to yield theepoxide.

99. A process according to claim 98 further comprisingesterifying an acid of formula (O) to generate the ester offormula II.

100. A process for preparing a compound of formula (XX)

(XX) wherein R57 is H, Cj-Ce alkyl, or benzyl; -85- 012597 is - (CH2)i-2-S(O)0-2-(Ci-C6 alkyl), -CH2-CH2-S (O) 0-2- (Ci-C6alkyl), or Ci-Cg alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen, -F, -Cl, -Br, -I, -OH, =0, -SH, -CsN, -CF3, -Ci-C3 alkoxy, araino,mono- or dialkylamino, -N(R) C (O) R'-, -OC(=0)-aminoand -OC(=0)-mono- or dialkylamino, or C2-Ce alkenyl or C2-C6 alkynyl, each of which is optionallysubstituted with 1, 2, or 3 groups independently selected from halogen, -F, -Cl, -Br, -I, -OH, -SH, -C=N, -CF3, Ci-C3 alkoxy, amino,' and mono- ordialkylamino, or aryl, heteroaryl, heterocyclyl, -Ci-C6 alkyl-aryl, -Ci-C6alkyl-heteroaryl, or -Ci-C6 alkyl-heterocyclyl, wherethe ring portions of each are optionally substitutedwith 1, 2, 3, or 4 groups independently selected fromhalogen, -F, -Cl, -Br, -I, -OH, -SH, -CsN, -NR7R'7,-C(=0) - (C1-C4) alkyl, -S02-amino, -S02-mono ordialkylamino, -C(=0)-amino, -C(=0)-mono or dialkylamino, -S02- (C1-C4) alkyl, -CO2R, -N(R)COR’, or-N(R)S02R'or -Ci-C6 alkoxy optionally substituted with 1, 2, or 3groups which are independently a selected fromhalogen, or C3-C7 cycloalkyl optionally substituted with 1, 2, or3 groups independently selected from halogen,-F, -Cl, -Br, -I, -OH, -SH, -CsN, -CF3, C1-C3 alkoxy, amino, -Ci-C6 alkyl and mono- ordialkylamino, or C1-C10 alkyl optionally substituted with 1, 2, or 3 groups independently selected from halogen, -F,-Cl, -Br, -I, -OH, -SH, -CsN, -CF3, -Ci-C3 -86- 012597 alkoxy, amino, mono- or dialkylamino and -C3-C3alkyl, or C2-C6 alkenyl or C2-C6 alkynyl, each of which isoptionally substituted with 1, 2, or 3 groupaindependently selected from halogen, -F, -Cl, - . Br, -I, -OH, -SH, -CsN, -CF3, C3-C3 alkoxy, amino, -Ci-Ce alkyl and mono- or dialkylamino;and the heterocyclyl group is optionally furthersubstituted with oxo; R, and R7' are independently H or -Ci-C6 alkyl; R2 and R3 are independently selected from the group consisting of H; Ci-Cg alkyl optionally substituted with one, two orthree substituents independently selected from the groupconsisting of C3-C3 alkyl, halogen, -OH, -SH, -CsN, -CF3, -Ci-C3 alkoxy, and -NR30R31; - (CH2) 0.4-aryl; - (CH2)0.4- heteroaryl; - (CH2) 0-4-heterocycle; C2-C6 alkenyl optionallysubstituted with one, two or three substituents independently selected from the group consisting of -F, -Cl, -OH, -SH, -CsN, -CF3, Ci-C3 alkoxy, and -NR30R3i; C2-Cgalkynyl optionally substituted with one, two or threesubstituents independently selected from the groupconsisting of -F, -Cl, tOH, -SH, -CsN, -CF3, C3-C3 alkoxy,and -NR3oR3i; and -{CH2)0-4- C3-C7 cycloalkyl, wherein thecycloalkyl group is optionally substituted with one, twoor three substituents independently selected from thegroup consisting of -F, -Cl, -OH, -SH, -CsN, -CF3, C3-C3alkoxy, and -NR3OR3i; or R2, R3 and the carbon to which they are attached form acarbocycle of three, four, five, six, or seven carbonatoms, wherein 1, 2, or 3 carbon atoms are optionally replaced by a heteroatom independently selected from thegroup consisting of -O-, -s-, -SO2-, and -NR22-; wherein -87- Gî2597 R30 and R3i at each occurrence are independently H, or Ci-C6alkyl; R22 is selected from the group consisting of -H, -Ci-Cfialkyl, hydroxy Ci-C6 alkyl, amino Ci-Cs alkyl; haloCi-C6 alkyl; -C3-C7 cycloalkyl, - (Ci-C2 alkyl) - (C3-C7cycloalkyl) , - (Ci-C6 alkyl) -0- (Ci-C3 alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl, -Ci-C6 alkyl chain with onedouble bond and one triple bond, aryl, heteroaryl,and heterocycloalkyl; Rc is selected from the group consisting of Ci-Ci0 alkyloptionally substituted with 1, 2, or 3 groupeindependently selected from the group consisting of R205,-OC=O NR23sR24o, -S(=0)o-2 R235, -NR23sC=O NR23sR24o, -C=0NR235R240» and -S(=0)2 NR23sR24o/ ~ (CH2) 0-3-(C3-Ca) cycloalkylwherein the cycloalkyl is optionally substituted with 1, "2, or 3 groups independently selected from the groupconsisting of R20s, -CO2H, and -C02- (C1-C4 alkyl); - (CR24SR250) 0-4-aryl ; - (CR24sR2so) 0-4-heteroaryl, - (CR24sR25o) 0-4“heterocycloalkyl; - (CR24SR250) 0-4-aryl-heteroaryl; -(CR245R2So) 0-4-aryl-heterocycloalkyl ; - (CR245R2S0) 0-4-aryl-aryl ; - (CR24sR2so) 0-4-heteroaryl-aryl ; - (CR24sR2so) o-4-heteroaryl -heterocycloalkyl; - (CR245R250) 0-4-heteroaryl-heteroaryl ; -(CR245R2so) 0-4-heterocycloalkyl-heteroaryl; - (CR245R2so) 0-4-heterocycloalkyl-heterocycloalkyl ; - (CR245R250) 0.4-heterocycloalkyl-aryl ; - [C (R2SS) (R2eo) ] i-3-CO-N-(R255) 2 ; -CH(aryl)2; -CH(heteroaryl)2; -CH(heterocycloalkyl)2 ; -CH(aryl)(heteroaryl); cyclopentyl, cyclohexyl, orcycloheptyl ring fused to aryl, heteroaryl, orheterocycloalkyl wherein one carbon of the cyclopentyl,cyclohexyl, or cycloheptyl is optionally replaced with ΝΉ,NR2is, O, or S (=0)0-2, and wherein the cyclopentyl,cyclohexyl, or -cycloheptyl group can be optionallysubstituted with 1 or 2 groups that are independently R20sor =0; -CO-NR23sR240 ; or -S02- (C1-C4 alkyl) ; C2-Cio alkenyl -88- ÛÎ2597 optionally substituted with 1, 2, or 3 R205 groupa; C2-Ci0alkynyl optionally substituted with 1, 2, or 3 R2os groups; ;- (CH2) o-i-CH ( (CH2) o-6-OH) - (CH2) o-i-aryl ; - (CH2) 0-i-CHRc.6- (CH2) 0- i-heteroaryl; -CH(-aryl or -heteroaryl)-C0-0(C1-C4 alkyl) ;-CH(-CH2-OH)-CH(OH)-phenyl-NO2, (Ci-C6 alkyl) -O- (Ci-C6alkyl)-OH, -CH2-NH-CH2-CH (-O-CH2-CH3) 2< -H, and -(CH2)0.6-C(=NR235) (NR235R240) ; wherein each aryl is optionally substituted with 1, 2, or 3 R2oo;each heteroaryl is optionally substituted with 1, 2, 3, or 4 R2oo7 èach heterocycloalkyl is optionally substituted with 1, 2,3, or 4 R21û; R20o at each occurrence is independently selected frora thegroup consisting of Ci-C6 alkyl optionallysubstituted with 1, 2, or 3 R20s groupe; OH; -N02;halogen; —CO2H; C>=N; - (CH2) o-4-CO-NR22oR22s; - (CH2) o-4~CO-(Ci-Cn alkyl); - (CH2) 0-4-CO- (C2-Ci2 alkenyl) ; -(CH2)0-4-C0- (C2-C12 alkynyl) ; - <CH2)0«,-CO- (C3-C7 cycloalkyl) ; - (CH2) o-4-CO-aryl ; - (CH2) 0-4-CO-heteroaryl ; - (CH2) 0.4-CO-heterocycloalkyl ; - (CH2) 0-4-CO-O-R2i5; - (CH2) 0-4-SO2-NR220R22S ; - (CH2) o-4“SO-(Cf-Ce alkyl); - (CH2) o-4“S02. (Ci-Ci2alkyl) ; - (CH2) 0-4-SO2- (C3-C7 cycloalkyl) ; - (CH2)0-4-N(Hor R215)-CO-O-R2i5; - (CH2) 0-4-N(H or R2is) -CO-N(R22s) 2} - (CH2)o-4-N-CS-N{R215)2; -(CH2)o.4-N(-H or R2is)-CO-R220; - (CH2)0-4-NR220R225; - (CH2)o-4-0-CO- (Cx-Ce alkyl); -(CH2)0-4-0-P(0) - (OR24o)2; - (CH2)o-4-0-CO-N(R2i5)2; - (CH2) 0-4-O-CS-N(R215)2; - (CH2) 0-4-O- (R215) 2; - (CH2) 0-4-O- (R215) a-COOH; - (CH2)0-4-S-(R2j.5) 2; - (CH2) 0-4-O- (Ci-C6 alkyl optionallysubstituted with 1, 2, 3, or 5 -F); C3-C7 cycloalkyl;C2-Ce alkenyl optionally substituted with 1 or 2 R2osgroups; C2-Ce alkynyl optionally substituted with 1or 2 R2o5 groups; - (CH2) 0-4-N (H or R215)-SO2-R22(>; and-{CH2)o-4- C3-C7 cycloalkyl; -89- 012597 wherein each aryl group at each occurrence is optionally substituted with 1, 2, or 3 groupsthat are independently R20s, R210 or Ci-C6 alkylsubstituted with 1, 2, or 3 groups that areindependently R20s or R2io; wherein each heterocycloalkyl group at each- occurrence is optionally substituted with 1, 2, or 3 groups that are independently R210;wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3 groupsthat are independently R205, R2io, or C!-C6 alkylsubstituted with 1, 2, or 3 groups that areindependently R20s or R2i0; R2o5 at each occurrence is independently selected from thegroup consisting of Ci-C6 alkyl, halogen, -OH, -O-phenyl, -SH, -CsN, -CF3, Ci-C6 alkoxy, NH2, NH(Ci-C6alkyl) , and N- (Ci-C6 alkyl) (Ci-Ce alkyl) ; R2io at each occurrence is independently selected from thegroup consisting of Ci-C6 alkyl optionallysubstituted with 1, 2, or 3 R20s groups; C2-Cs alkenyloptionally substituted with 1, 2, or 3 R20S groups;C2-C6 alkynyl optionally substituted with 1, 2, or 3R20S groups; halogen; Ci-C6 alkoxy; Ci~C6 haloalkoxy;-NR220R225; OH; CsN; C3-C7 cycloalkyl optionallysubstituted with 1, 2, or 3 R2os groups; -CO-(C1-C4alkyl) ; .S02,NR23sR24o; -CO-NR23sR24o; -SO2- (C1-C4 alkyl) ;and =0; wherein R2i5 at each occurrence is independently selected fromthe group consisting of Ci-C6 alkyl, -(CH2)0-2-(aryl), C2-C6 alkenyl, C2-C6 alkynyl, C3.C7cycloalkyl, and - (CH2) 0-2- (heteroaryl) , -(CH2)0-2-(heterocycloalkyl); wherein the aryl group at .each occurrence is optionally substituted with -90- f ' 012597 1, 2, or 3 groupa that are independently R20s orR210; wherein the heterocycloalkyl group at eachoccurrence is optionally substituted with 1, 2,or 3 R2io; wherein each heteroaryl group at each 5 occurrence is optionally substituted with 1, 2, or 3 R210; R220 and R225 at each occurrence are independently selected from the group consisting of -H, -Ci~C6alkyl, hydroxy Ci-Ce alkyl, amino Ci-C6 alkyl; 10 halo Ci-Ce-alkyl/ -C3-C7 cycloalkyl, - (Ci-C2 alkyl) - (C3-C7 cycloalkyl), - (Cj-Ce alkyl)-O-(C1-C3alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl, -Ci-C6alkyl chain with one double bond and one triplebond, -aryl, -heteroaryl, and -heterocycloalkyl; 15 wherein the aryl group at each occurrence is optionally substituted with 1, 2, or 3groupe that are independently R205 or R210; wherein the heterocycloalkyl group at each occurrence is optionally substituted with 20 1, 2, or 3 R210; wherein each heteroaryl group at each occurrence is optionally substituted with 1, 2, or 3R210 ; R235 and R240 at each occurrence are independently H, or Ci- 25 C6 alkyl; R245 and R2so at each occurrence are independently selectedfrom the group consisting of H, C1-C4 alkyl, C1-C4hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, - (CH2) 0- 4-C3-C7 cycloalkyl, C2-C6 alkenyl, C2-Cg alkynyl, and 3 0 phenyl; or R245 and R250 are taken together with the carbon to which they are attached to form a carbocycle of 3, 4, 5, 6,or 7 carbon atoms, optionally where one carbon atom -91- 012597 is replaced by a heteroatom selected from the groupconsisting of -O-, -S-, -S02-, and -NR220-; r255 and Rj6o at each occurrence are independently selectedfrom the group consisting of H; Ci-C6 alkyloptionally substituted with 1, 2, or 3 R20s groups;C2-C6 alkenyl optionally substituted with 1, 2, or 3R205· groups; C2-C6 alkynyl optionally substituted with1, 2, or 3 R2os groups; - (CH2) i-2-S (O) 0-2- (Ci-C6 alkyl) ; - (CH2) 0-4-C3-C7 cycloalkyl optionally substituted with1, 2, or 3 R205 groups; - (C1-C4 alkyl)-aryl; - (C1-C4alkyl) -heteroaryl; - (C3.-C4 alkyl) -heterocycloalkyl;-aryl; -heteroaryl; -heterocycloalkyl; - (CH2) i-4-R26S-(CH2) 0-4-aryl; - (CH2) 1-4-R265- (CH2) 0-4-heteroaryl; and; - (CH2) 1-4-R265- (CH2)0-4-heterocycloalkyl; wherein R2es at each occurrence is independently -0-, -S- or-N(Ci-C6 alkyl)-; each aryl or phenyl is optionally substituted with 1,2, or 3 groups that are independently R20s, R210/or Ci-Cg alkyl substituted with 1, 2, or 3groups that are independently R205 or R2i0; each heteroaryl is optionally substituted with 1, 2,3, or 4 R2oo/ each heterocycloalkyl is optionally substituted with1, 2, 3, or 4 R2io» Rn is -C (=0) - (CRR* ) o-eRioo» R'iooz -S02R'ioo, - (CRR' ) i-gR' 100»-C(=O) - (CRR')-O-R'xoo, -C(=0)-(CRR')-S-R'xoo or -C(=0)-(CRR' ) -NRloo-R'ioo; R100 and R'100 are independently aryl, heteroaryl, -aryl-W-aryl,-aryl-W-heteroaryl, -aryl-W-heterocyclyl, -heteroaryl-W-aryl, -heteroaryl-W-heteroaryl, -heteroaryl-W- heterocyclyl, -heterocyclyl-W-aryl, -heterocyclyl-W-heteroaryl, -heterocyclyl-W-heterocyclyl, -C (=0)-CH [ (CH2) 0-2-O-R7] - (CH2) 0-2-aryl, -C (=0) -CH ( (CH2) o-2-0-R7] - (CH2) 0-2-heterocyclyl, or -C (=0) -CH [ (CH2) 0-2-O-RJ - (CH2) 0-2- -92- Û12597 heteroaryl, where the ring portions of each are optionallysubstituted with 1, 2, or 3 groupe independently selectedfrom -OR, -N02, halogen, -CsN, -SR, -S02R14S, -C(=O)R, -OCF3, -CF3, -0-P(=0) (OR} (OR' ) , -N(R) (COR’ ) , -N (R) (SO2Rx45) . - (ÇH2)0_4-CO-NR105R'10s, ~ (CH2) o-4“0- (CH2) o-4-CONRR', - (CH2) o-4-CO- (Ci-C12 alkyl) , - (CH2) 0.4-CO- (C2-Cx2alkenyl), - (CH2) 0-4-CO-(C2-C12 alkynyl) , -(CH2)0-4-CO-(C3-C7 cycloalkyl), - (CH2)o-4-Ruo, - (CH2) O-4-R120, - (CH2) o-<-Ri3o» ~ (CH2) o-4“CO-Rho, “ (CH2) o-4~CO-Ri2o, - (CH2) o-4_CO-Ri3o, - (CH2) o-4-CO-Ri40, - (CH2) o-4~CO-0-Rxso, - (CH2) o-4-S02-NRio5R'iûs, - (CH2) 0-4-SO- (Cx-C8 alkyl) , - (CH2) 0.4-SO2. (Ci-C12 alkyl) , - (CH2) 0.4-SO2- (C3-C7cycloalkyl) , - (CH2) 0.4-N (H or R1So) -CO-O-Ri50, - (CH2) 0-4-N(H or Rxso)-CO-N(Ri50)2, - (CH2) 0-4"N(H or R1S0)-CS-N(Rx50)2, - (CH2) o-4-N (-H or Rxso)-CO-Rxos, -(CH2)o-4~NRxosR'xos, - (CH2)o-4-Rx4o, -(CH2)o_4-0-CO-(Cx-C6 alkyl), - (CH2)0.4-O-P(O) - (0-Rxxo)2, - (CH2) ο-,-O-CO-N (Rxso) 2, - (CH2) o-4~0~CS-N(Rxso) 2, - (CH2) 0-4-O- (Rxso) , - (CH2) o-4~0_(Rxss)-COOH, - (CH2)o-4“S-(Rxso) , C3-C7 cycloalkyl, - (CH2) o-4~N(-H or Rxso)-SO2-R7, or -(CH2)o-4~ C3-C7cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or Rxoo is Cx-Cxo alkyl optionally substituted with 1, 2, or 3 RxxSgroupa, wherein Rxxs at each occurrence is independently halogen, -OH, -CO2R, -Cx-C6 thioalkoxy, -CO2-phenyl, -NRiosR'7, -S02-(Cx-Cg alkyl) , -C (=0) Rxso, Rxeo, -CONRxosR' xos, -S02NRxosR' xos, -NH-CO-(Ci-C6 alkyl) , -NH-C(=0)-OH, -NH-C(=0)-OR, -NH-C(=0)-O-phenyl, -O-C(=O)-(Cx-C6 alkyl),-O-C(=O)-amino, -O-C(=O)-mono- or dialkylamino, -O-C(=O) -phenyl, -O-(Cx-C6 alkyl)-CO2H, -NH-SO2-(Cx-Cfialkyl) , Cx-C6 alkoxy or Cx-Ce haloalkoxy; or -93- 012597 Rxoo is - (Ci-C6 alkyl)-0-(Ci-C6 alkyl) or - (Cx-C6 alkyl)-S-(Cx-C6alkyl), each of which is optionally substituted with 1, 2,or 3 Rus groups, or Rxoo is - (C3-Ce cycloalkyl) optionally substituted with 1, 2, or3 Rus groups; R and R' independently are hydrogen; Cx-C6 alkyl optionally substituted with 1, 2, or 3 groups that are independentlyF, Cl, Br, or I; or - (Cx-C6) -Rx10; W is -(CH2)o-4-/ -O-, -S (O) ο-a-, -N(Ri3s)-, or -C(O)-; R7 and R7' are independently selected from the group consistingof H, Cx-C6 alkyl, C3-C7 cycloalkyl, C2-C6 alkenyl, C2-C6alkynyl, aryl, heteroaryl, and heterocyclyl, R105 and R'xos are the same or different and represent -H, -Rx10,-Rx2o, -C3-C7 cycloalkyl, - (Cx-C2 alkyl) - (C3-C7 cycloalkyl), - (Cx-Cs alkyl)-O-(Cx-C3 alkyl), -C2-C6 alkenyl, -C2-C6'alkynyl, or -Cx-C6 alkyl chain with one double bond andone triple bond, or -Cx-C6 alkyl optionally substituted with -OH or -NH2; or, -Ci-C6 alkyl optionally substituted with 1, 2, or 3 groupsindependently selected from halogen; Ri35 is Cx-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3.C7 cycloalkyl, - (CH2) 0-2- (aryl) , - (CH2)0.2-(heteroaryl) , or - (CH2)0-2- (heterocyclyl) , R140 is heterocyclyl optionally substituted with 1, 2, 3, or 4groups independently selected from Cx~C6 alkyl, Cx-C6alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(Cx-C6) alkylamino, di (Cx-C6) alkylamino, C2-C6 alkenyl, C2-C6alkynyl, Cx~C6 haloalkyl, Cx-C6 haloalkoxy, amino (Cx-C6) alkyl, mono (Cx-C6) alkylamino (Cx-C6) alkyl, di(Cx-C6) alkylamino (Cx-C6) alkyl, and =0; R145 is Cx-C6 alkyl or CF3; R150 is hydrogen, C3-C7 cycloalkyl, - (C2-C2 alkyl) - (C3-C7 cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, Cx-C6 alkyl withone double bond and one triple bond, -Rx10, -Ri2o, or -94- 012597 Ci-Ce alkyl optionally substituted with 1, 2, 3, or 4 groupa independently selected from -OH, -NH2, C1-C3alkoxy, Ru0, and halogen; Riss is C3-C7 cycloalkyl, - (Cx-C2 alkyl) - (C3-C7 cycloalkyl), C2-Csalkenyl, C2-C6 alkynyl, Ci-Ce alkyl with one double bondand one triple bond, -Ruo, -Ri2o, or Ci-C6 alkyl optionally substituted with 1, 2, 3, or 4 groupa independently selected from -OH, -NH2, C1-C3alkoxy, and halogen; Rieo is selected from morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl, homomorpholinyl, homothiomorpholinyl,homothiomorpholinyl S-oxide, homothiomorpholinyl S,S- dioxide, pyrrolinyl and pyrrolidinyl, each of which isoptionally substituted with 1, 2, 3, or 4 groupa independently selected from Ci-C6 alkyl Ci-C6 alkoxy,halogen, hydroxy, cyano, nitro, amino, mono(Ci-C6) alkylamino, di (Ci-C6) alkylamino, C2-Ce alkenyl, C2-C6alkynyl, Ci-C6 haloalkyl, Ci-C6 haloalkoxy, amino(Ci-C6) alkyl, mono (Ci-C6) alkylamino (Ci-C6) alkyl, di(Cx- C6) alkylamino (Ci-C6) alkyl, and -O;Rn0 is aryl optionallysubstituted with 1 or 2 R125 groupe, wherein, R125 at each occurrence is independently halogen, amino,mono- or dialkylamino, -OH, -CsN, -SO2-NH2, -SO2-NH-Ci-Ce alkyl, -SO2-N(CX-C6 alkyl)2, -SO2- (C1-C4 alkyl), -CO-NH2, -CO-NH-Ci-Ce alkyl, or -CO-N(CX-CS alkyl) 2; orCi-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1, 2, or 3groups that are independently selected from Cx-C3 alkyl, halogen, -OH, -SH, -CsN, -CF3, Cx-C3alkoxy, amino, and mono- and dialkylamino; or Ci-Ce alkoxy optionally substituted with one, two orthree of halogen; _ -95- 012597 Ri2o is heteroaryl, which is optionally substituted with 1or 2 R125 groupe; and R130 is heterocyclyl optionally substituted with 1 or 2 R125groups; comprising (a) reducing a ketone of formula III to generate analcohol of formula IV; and (b) treating the alcohol of formula IV with a base togenerate an epoxide.

101. A process according to claim 100, further comprisingcontacting the epoxide with an amine of formula RcNH(RS7) toyield a protected amine of formula VII-1.

102. A process according to claim 101, further comprisingformirig a deprotected amine of formula VIII-1 and forming anamide using the amine of formula VIII-1 and a compound of theRnCOZ, wherein Z is OH, Cl, or imidazolyl.

103. An amino alcohol of the formula:

where R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Ci-C6 alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, thio, -NR10Rn where R10 andRu are indepehdently hydrogen or Ci-Ce alkyl, cyano,trifluoromethyl, and Ci-C3 alkoxy, (B) C2-C6 alkenyl or C2-C6 alkynyl, -96- 012597 10 15 20 25 30 (C) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallÿsubstituted with 1, 2, or 3 fluoro, (D) -NR12R13 where at each occurrence Ri2 and Ri3 are the same or different and represent; (a) -H, (b) -Ci-CB alkyl optionallÿ substituted with one of: (i) -OH, (ii> -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionallÿ substituted with 1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, - (Ci~C2 alkyl) - (C3-C8cycloalkyl), - (Ci-C6 alkyl)-O-(Ci-C3 alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl; and (E) C3-C7 cycloalkyl, -C{0) (Cx-C4 alkyl), -SO2NRi0Rii, -C (O) NR10R11, or -S02 (C1-C4 alkyl); and R2 is : chloro, brotno, or -Si(R2i)3 where each R2i is independently Cx-Cs· alkyl, -N(R23) (R24) where R23 and R24 are the same ordifferent and represent Cx-Cs alkyl, or where NR23R24 représente piperidinyl,piperazinyl, or morpholinyl, phenyl optionallÿ substituted with 1, 2, or 3 of Ci-C2 alkyl, with the proviso that at least one ofthe R2i groups is optionallÿ substituted phenyl.

104. A compound of the formula

105. A compound of the formula

where Xi is chloro, bromo, or imidazolyl, or Xi is —CH2-R2, where in -98- 012597 R2 is chloro, bromo, or-Si(R2i)3 where each R2i is independently Ci-C5 alkyl, -N(R23) (R2«) where R23 and R24 are the same ordifferent and represent Ci-Cs alkyl, or where NR23R24 représente piperidinyl,piperazinyl, or morpholinyl, phenyl optionally substituted with 1, 2, or 3 of Ci-C2 alkyl, with the proviso that at least one ofthe R21 groupe is optionally substituted phenyl; R is phenyl optionally substituted with 1, 2, 3, or 4 groupeindependently selected from: (A) Ci-Ce alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, thio, -NRX0Rn where R10 andRu are independently hydrogen or Ci-Cfi alkyl, cyano,trifluoromethyl, and Cx-C3 alkoxy, (B) C2-C6 alkenyl or C2-C8 alkynyl, (C) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NR12R13 where at each occurrence Rx2 and Ri3 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of: (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Cx-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, - (Cx-C2 alkyl) - (C3-C8cycloalkyl), -(Cx-Cg alkyl)-O-(Cj-C3 alkyl), -C2-C6 alkenyl, -C2-Cg alkynyl; and -99- 012597 (E) C3-C7 cycloalkyl, -C(0) (C1-C4 alkyl) , -SO2NRi0Rh, -C(O)NRioRn, or -SO2(Ci-C4 alkyl); and PROT is a nitrogen protecting group.

106. A compound of the formulaO^zORi f^^N-PROT R wherein Ri is selected from: (I) Ci-Ce alkyl optionally substituted with one halogen; (II) - CH2-CH=CH2; (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on phenyl with nitro,halogen, or cyano R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Ci-Ce alkyl optionally substituted with one, two orthree substituents independently selected from C1-C3alkyl, halogen, hydroxy, thio, -NR10R11 where Rio andRu are independently hydrogen or Ci-C6 alkyl, cyano,trifluoromethyl, and C1-C3 alkoxy, (B) C2-Ce alkenyl or C2-C6 alkynyl, (C) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NR12Ri3 where at each occurrence Ri2 and R13 are the same or different and represent: (a) -H, (b) -Ci-Ce alkyl optionally substituted with one of: (i) -OH, (ii) -NH2, (iii) phenyl, -100- 012597 (c) -Ci-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, - (Ci-C2 alkyl)-(C3-CBcycloalkyl) , - (Ci-C6 alkyl)-O-(C3-C3 alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl; and (E) C3-C7 cycloalkyl, -C(O) (Cx-C4 alkyl), -SO2NRi0Rii, -C(O)NRioRu, or -SO2(Ci-C4 alkyl); andPROT is a nitrogen protecting group.

107. A procèss for preparing compounds of the formula PROT

wherein Ri is selected from: (I) Ci-C6 alkyl optionally substituted with one halogen; (II) ~CH2-CH=CH2 ; (III) phenyl optionally substituted with one nitro,halogen, or cyano; andl (IV) benzyl optionally substituted on phenyl with nitro,halogen, or cyano; the process comprises (1) esterifying a prôtected amino acid of the formula H protxN ΌΗ wherein R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Ci-Ce alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, thio, -NR10Rn where R10 and -101- 0.12597 Rxx are independently hydrogen or Cx-Cs alkyl, cyano,trifluoromethyl, and C1-C3 alkoxy, (B) C2-C6 alkenyl or C2-Ce alkynyl, (C) halogen, hydroxy, cyano, Cx-C6 alkoxy optionally 5 substituted with 1, 2, or 3 fluoro, (D) -NR12R13 where at each occurrence Ri2 and R13 are the same or different and represent: (a) -H, (b) -Ci-Ce alkyl optionally substituted with one of: 10 (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, 15 (d) -C3-C8 cycloalkyl, - (Cx-C2 alkyl) - (C3-C8 cycloalkyl) , - (Cx-C6 alkyl)-O-(Cx-C3 alkyl), -C2-C6 alkenyl, -C2-Ce alkynyl; and (E) C3-C7 cycloalkyl, -C(O) (Cx-C4 alkyl) , -SO2NRx0Rix,-C(O)NR10Rxi, or -SO2(Cx-C4 alkyl); and 20 PROT is a nitrogen protecting group; with an alkylating agent in the presence of a base.

108. A process for preparing compounds of the formula: PROT

109. A method for preparing a compound of the formula -103- 012597

where R3 is selected frora: (I) Ci-C6- alkyl optionally substituted with one halogen; (II) -CH2-CH=CH2; (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on phenyl with nitro,halogen, or cyano; R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) C1-C5 alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, thio, -NRi0Rn where R10 andRu are independently hydrogen or Ci-C6 alkyl, cyano,trifluoromethyl, and Ci-C3 alkoxy, (B) C2-C6 alkenyl or C2-C6 alkynyl, (C) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NRi2Ri3 where at each occurrence Ri2 and RX3 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of: (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, -(Ci-C2 alkyl) - (C3-C8cycloalkyl) , - (Ci-C6 alkyl) -O- (Ci-C3 alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl; and -104- 012597 (E) C3-C7 cycloalkyl, -C(O) {C3-C4 alkyl) , -SO2NRi0Ru, -C{O)NR10Rn» or -SO2(C3-C4 alkyl); and PROT is a nitrogen protecting group;the process comprising: A) reducing a compound of the formula

with a reducing agent.

110. A method according to daim 109 wherein the reducingagent is NaBH4, NaCNBH3, or hydrogen and a catalyst..

111. A method according to claim 110 wherein the reducingagent-is hydrogen and a catalyst.

112. A method according to claim 111 wherein thehydrogénation is carried out at a pressure of from 1 atmosphèreto about 100 psi.

113. A method for preparing a compound of the formula

where R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Ci-Cé alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, thio, -NRi0Ru where R10 andRu are independently hydrogen or Cj.-C6 alkyl, cyano,trifluoromethyl, and Ci-C3 alkoxy, -105- 012597 (B) C2-C6 alkenyl or C2-C6 alkynyl, (C) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NR12R13 where at each occurrence Ri2 and R13 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of: (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) -C3-Cs cycloalkyl, - (Ci-C2 alkyl) - (C3-C8cycloalkyl) , - (Ci-C6 alkyl)-O-(Ci-C3 alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl; and (E) C3-C7 cycloalkyl, -C(O)(Ci-C4 alkyl), -SO2NRi0Rxi, -C (O) NRioR-ii, or -SO2(Ci-C4 alkyl) ; R2 is : chloro, bromo, or -Si(R2i)3 where each R21 is independently Ci-C5 alkyl, -N(R23) (R24) where R23 and R24 are the same ordifferent and represent Ci-C5 alkyl, or where NR23R24 représente piperidinyl,piperazinyl, or morpholinyl, phenyl optionally substituted with 1, 2, or 3 of Cx-C2 alkyl, with the proviso that at least one ofthe R2i groups is optionally substituted phenyl; and PROT is a nitrogen protecting group; which comprises: (a) forming a mixture of an ester of the formula -106- 012597 PROT

wherein Ri is selected from: (I) Ci-Cg alkyl optionally substituted with one halogen; (II) -CH2-CH=CH2; (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on phenyl with nitro,halogen, or cyano; and R2CH2Xa, where R2 is as de£ined above, andX2 is -Br or -I; (b) adding a strong base having a pKb of greater thanabout 30 to the mixture from (a); (c) acidifying the mixture of (b).

114. A method for preparing a compound of the formula R2

where R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Ci-C6 àlkyl optionally substituted with one, two orthree substituents independently selected from C1-C3alkyl, halogen, hydroxy, thio, -NR10Rn where R10 andRu are independently hydrogen or Ci-C6 alkyl, cyano,trifluoromethyl, and C1-C3 alkoxy, (B) C2-Cg alkenyl or C2-C6 alkynyl, -107- 01259? (C) halogen, hydroxy, cyano, Ci~C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NR12R13 where at each occurrence R12 and Ri3 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of : (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) —C3-C8 cycloalkyl, - (Ci-C2 alkyl) - (C3-C8 cycloalkyl), - (Cj.-C6 alkyl)-Ο-(Ο3-Ο3 alkyl), -C2-C6 alkenyl, -C2-C6 alkynyl; and (E) C3-C7 cycloalkyl, -0(0)(0Χ-04 alkyl), -SO2NR10Rn, -C(O)NR10Ru, or -SO2(Ci-C4 alkyl); R2 is: chloro, bromo, or -Si(R2x)3 where each R2X is independently Cx-C5 alkyl, -N(R23) (R24) where R23 -and R24 are the same ordifferent and represent C1-C5 alkyl, or where NR23R24 représente piperidinyl,piperazinyl, or morpholinyl, phenyl optionally substituted with 1, 2, or 3 of Cx-C2 alkyl, with the proviso that at least one ofthe R2i groups is optionally substituted phenyl; and PROT is a nitrogen protecting group; which comprises: (a) forming a mixture of an acid R2-CH2-COOH and a base, (b) treating the mixture of (a) with an ester of theformula -108- û 12597 PROT

wherein R, and PROT are defined above, andRi is selected from: (I) Ci-Cs alkyl optionally substituted with onehalogen; (II) -CH2-CH=CH2; (III) phenyl optionally substituted with one nitro,halogen, or cyano; and (IV) benzyl optionally substituted on phenyl withnitro, halogen, or cyano; (c) acidifying the mixture from (b).

'115. A method according to claim 114 wherein, the base hasa pKb 30 or greater.

116. A method for preparing a compound of the formula

wherein R is phenyl optionally substituted with 1, 2, 3, or 4 groupsindependently selected from: (A) Ci-Ce alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, thio, -NRi0Ru where Rio andRu are independently hydrogen or Ci-C6 alkyl, cyano,trifluoromethyl, and C1-C3 alkoxy, (B) C2-C6 alkenyl or C2-Ce alkynyl, (C) halogen, hydroxy, cyano, Cx-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro. -109- 012597 (D) -NR12R13 where at each occurrence R12 and R13 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of: (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionally substituted with .1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, - (Cx-C2 alkyl) - (C3-C8cycloalkyl), - (Ci-C6 alkyl) -O- (Ci-C3 alkyl), -C2-C6 alkenyl, -C2-C8 alkynyl; and (E) C3-C7 cycloalkyl, -C(O) (C!-C4 alkyl), -SO2NRi0Rh, -C (O)NRioRn, or -SO2(Ci-C4 alkyl); R2 is Cl or Br; and PROT is a nitrogen protecting group; which comprises contacting a compound of the formula PROT-N

wherein Xi is chloro, bromo, or imidazolyl;with LiCH2Cl or LiCH2Br.

117. A method for preparing a compound of the formulaO PROT- wherein Xi is chloro, bromo, or imidazolyl; R is phenyl optionally substituted with 1, 2, 3, or 4 groups · independently selected from: 110- 012597 (A) Ci-C6 alkyl optionally substituted with one, two orthree substituents independently selected from Ci-C3alkyl, halogen, hydroxy, thio, -NR10Rn where Rxo andRu are independently hydrogen or Cx-Ce alkyl, cyano,trifluoromethyl, and Cx-C3 alkoxy, (B) C2-C6 alkenyl or C2-C6 alkynyl, (C) halogen, hydroxy, cyano, Ci-C6 alkoxy optionallysubstituted with 1, 2, or 3 fluoro, (D) -NR12R13 where at each occurrence Ri2 and R13 are the same or different and represent: (a) -H, (b) -Ci-C8 alkyl optionally substituted with one of : (i) -OH, (ii) -NH2, (iii) phenyl, (c) -Ci-C8 alkyl optionally substituted with 1, 2, or 3 independently selected halogens, (d) -C3-C8 cycloalkyl, - (Cj.-C2 alkyl) - (C3-C8cycloalkyl) , -(Cx-Ce alkyl)-0-(Cx-C3 alkyl), -C2-Ce alkenyl, -C2-C6 alkynyl; and (E) C3-C7 cycloalkyl, -C(O)(Cx-C4 alkyl), -SO2NR10Rn« -C (O) NRioRn, or -SO2(Ci-C4 alkyl); and PROT is a nitrogen protecting group; which comprises contacting a compound of the formula PROT

with thionyl chloride, phosphorous trichloride, oxalylchloride, phosphorous tribromide, triphenylphosphorousdibromide, oxalyl bromide, 1,2-phenylenetrichlorophosphate,2,4,6-trichloro-l,3,5-triazine or carbonyldiimidazole. -111-